Triazolone  compounds and uses thereof

ABSTRACT

The invention disclosed herein is directed to compounds of Formula I 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, which are useful in the treatment of prostate, breast, colon, pancreatic, human chronic lymphocytic leukemia, melanoma and other cancers. The invention also comprises pharmaceutical compositions comprising a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof. The invention disclosed herein is also directed to methods of treating prostate, breast, ovarian, liver, kidney, colon, pancreatic, human chronic lymphocytic leukemia, melanoma and other cancers. The invention disclosed herein is further directed to methods of treating prostate, breast, colon, pancreatic, chronic lymphocytic leukemia, melanoma and other cancers comprising administration of a therapeutically effective amount of a selective PPARα antagonist. The compounds and pharmaceutical compositions of the invention are also useful in the treatment of viral infections, such as HCV infections and HIV infections.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patentapplication No. 61/739,906 entitled “TRIAZOLONES COMPOUNDS AND USESTHEREOF” filed on Dec. 20, 2012, which is incorporated by reference inits entirety.

FIELD OF THE INVENTION

This invention is directed to novel triazolones, or pharmaceuticallyacceptable salts thereof, useful in the treatment of prostate, breast,colon, pancreatic, human chronic lymphocytic leukemia, melanoma andother cancers. The invention disclosed herein is further directed tomethods of treating prostate, breast, ovarian, liver, kidney, colon,pancreatic, human chronic lymphocytic leukemia, melanoma and othercancers comprising administration of selective PPARα antagonists. Thecompounds and pharmaceutical compositions of the invention are alsouseful in the treatment of viral infections, such as HCV infections andHIV infections.

BACKGROUND OF THE INVENTION

While tremendous strides have been made in the treatment of variouscancers, in many cases, cancer treatment continues to be a matter ofadministering one or more anti-cancer agents that are marginally lesschemotoxic to healthy cells than they are to the cancer in question. Inrecognition of this problem, there has been substantial research effortaimed at identifying, understanding and taking advantage of phenotypicalbehavior peculiar to certain cancer cells. It has long been observedthat most cancer cell types generate energy for cellular processesthrough aerobic glycolysis rather than through oxidative phosphorylationas found in the normal cell. This process, which became known as the“Warburg effect”, is highly energy inefficient and requires cancer cellmitochondria to resort to glucose fermentation to make up the energydeficit. Since perhaps the mid-1990's researchers have sought toidentify methods of treating cancer that take advantage of the “Warburgeffect” and associated aspects of cancer cell mitochondrial metabolism.See, for example, Wang, et al., Small mitochondrial-targeting moleculesas anti-cancer agents, Mol. Aspects Med. 2010 February; 31(1): 75-92.

Samudio, et al., J. Clin. Invest. 120: 142-156 (2010), disclosed that incertain leukemia cell lines “mitochondrial uncoupling—the continuingreduction of oxygen without ATP synthesis—has recently been shown inleukemic cells to circumvent the ability of oxygen to inhibitglycolysis, and may promote the metabolic preference for glycolysis byshifting from pyruvate oxidation to fatty acid oxidation (FAO).”Samudio, et. al., also provided data indicating that inhibition of FAOcould sensitize human leukemia cells to apoptosis, and further thatinhibition of FAO may prove useful in the treatment of leukemia.

PPARα is known to be an important regulator of fatty acid oxidation. SeePyper, et al., Nucl. Recept. Signal. 8:e002, e002 (2010). It has beenreported that the expression of the PPARα gene can be higher in humanchronic lymphocyte leukemia (CLL) making this cancer type sensitive totherapies aimed at reducing FAO (Samudio et al., J. Clin. Invest.120:142-156 (2010)). This effect may generalize to several cancer types.For example, ovarian cancer and breast cancer (Linher-Melville et al.,2011, BMC, 4; 11:56), thrive in an adipose rich environment and as aresult can be negatively impacted by targeted therapies that reducefatty acid metabolism (Nieman et al., 2011, Nat Med. 2011 Oct. 30;17(11):1498-503). Still other cancers that rely on FAO include prostatecancer (Liu, Prostate Cancer Prostatic Dis. 2006; 9(3):230-4), coloncancer (Holla et al., 2011, JCB 286(34):30003-30009), pancreatic cancer(Khasawneh et al., 2009, PNAS 106(9):3354-3359) and lung cancer (Zaugget al., 2011, Genes and Development, 25:1041-1051).

GW6471 (Xu et al., Nature 415, 813-817 (2002) and MK-866 (Kehrer et al.,Biochem. J. 356, 899-906 (2001) have been identified as antagonists ofPPARα. Moreover, MK-866, whose primary activity is as an inhibitor ofFLAP, has been disclosed to induce apoptosis in a human chroniclymphocytic leukemia cell line in a FLAP-independent manner; and hasalso been disclosed to induce apoptosis in prostate and glioblastomacell lines.

It is our belief that in cancers that rely heavily on FAO, antagonism ofPPARα by small molecules provides a panoply of anti-cancer treatmentopportunities to: reduce or halt proliferation; decrease or reverseimmunosupression; enhance apoptosis; and increase susceptibility ofcancerous cells to other anti-cancer agents. These cancers includeprostate, breast, colon and pancreatic cancer, among others.

Chronic myeloid leukemia (CML) is model of hematopoietic stem cell (HSC)disease. In 2008, Ito et al. disclosed evidence linking the loss ofpromyelocytic leukemia (PML) gene expression with favorable outcomes inCML (Nature, 2008 June 19; 453 (7198) 1072-1078). More recently Ito etal. disclosed that in the PML pathway, loss of PPAR6 and accompanyinginhibition of mitochondrial FAO induced loss of hematopoietic stem cell(HSC) maintenance (Nature Medicine, doi:10.1038/nm.2882). Moreover,Carracedo et al. disclosed that whereas PML expression allowed luminalfilling in 3D basement membrane breast cancer, the effect was reversedby inhibition of FAO (J. Clin. Invest. 2012; 122(9):3088-3100). This andother evidence supports our view that inhibition of fatty acidoxidation, via antagonism of PPAR's (including PPARα), will proveeffective in inhibiting asymmetric leukemia stem cell differentiation,and therefore, prove effective in preventing the onset of and/orrecurrence of acute and chronic myeloid leukemia, as well as othercancers.

PPARα antagonists have also been shown to inhibit HCV replication andthereby prove useful in the treatment of HCV infection (Rakic et al.,Chem. & Biol. 13, 23-30 (January 2006)). In some embodiments, PPARmodulators have been shown to inhibit viral transcription andreplication and thereby prove useful in the treatment of viral diseases(Capeau et al., PPAR Research Volume 2009, Article ID 393408, 2 pages).In some embodiments, PPARα antagonists are useful in the treatment ofHIV infection. PPARα antagonists have also been disclosed to be usefulin the treatment of metabolic disorders (WO2012/027482A2). Metabolicdisorders include, but are not limited to diabetes, obesity, metabolicsyndrome, impaired glucose tolerance, syndrome X, and cardiovasculardisease.

SUMMARY OF THE INVENTION

The invention disclosed herein is directed to compounds of Formula I

and pharmaceutically acceptable salts thereof, which are useful in thetreatment of prostate, breast, colon, pancreatic, human chroniclymphocytic leukemia, melanoma, and other cancers. The invention alsoincludes pharmaceutical compositions comprising a therapeuticallyeffective amount of compound of Formula I, or a pharmaceuticallyacceptable salt thereof. The invention disclosed herein is also directedto methods of treating prostate, breast, ovarian, liver, kidney, colon,pancreatic, human chronic lymphocytic leukemia, melanoma and othercancers. The invention disclosed herein is further directed to methodsof treating prostate, breast, ovarian, liver, kidney, colon, pancreatic,human chronic lymphocytic leukemia, melanoma and other cancers throughthe administration of a therapeutically effective amount of a selectivePPARα antagonist. The compounds and pharmaceutical compositions of theinvention are also useful in the treatment of viral infections, such asHCV infections and HIV infections.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the ability of Example 6 to inhibit the metastasis ofB16F10 melanoma cells to the lung.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention is directed to a compound of Formula I

or a pharmaceutical acceptable salt thereof wherein:A1 is phenyl or a 6-membered heteroaromatic ring having 1, 2 or 3 N inthe heteroaromatic ring;A2 is selected from A2a or A2b

wherein A2a is phenyl or a 6 membered heteroaromatic ring having 1, 2 or3 N in the heteroaromatic ring, and A2b is a 5 membered heteroaromaticring having 1, 2 or 3 heteroatoms independently selected from O, S andN;X is selected from the group consisting of —(CH₂)_(m)—,—(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—NH—(CH₂)_(n)—,—(CH₂)_(m)—S(═O)_(o)—(CH₂)_(n)—, optionally mono- or di-substituted withhalogen, wherein m and n are independently 0, 1, 2, 3 or 4, and each ois independently 0, 1 or 2;

Y is O or S;

R¹ and R² are each independently selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) halogen,    -   (c) CN,    -   (d) CF₃,    -   (e) —C₁₋₆alkyl,    -   (f) —C₁₋₆alkyl-C(═O)OH,    -   (g) —O—(R⁷),    -   (h) —S(═O)_(o)R⁷,    -   (i) —N(R⁷)(R⁸),    -   (j) —N(R⁷)—C(═O)—(R⁸),    -   (k) —N(R⁷)—C(═O)—O—(R⁸),    -   (l) —N(R⁷)S(═O)₂(R⁸),    -   (m) —C₃₋₆cycloalkyl,    -   (n) —C(═O)(R⁷),    -   (o) aryl,    -   (p) heteroaryl,    -   (q) —OC(═O)N(R⁷)(R⁸),    -   (r) —S(═O)₂N(R⁷)(R⁸),    -   (s) —C(═O)N(R⁷)(R⁸), and    -   (t) —C(R⁷)(R⁸)OH,        wherein the alkyl portion of choices (e) and (f), and the        cycloalkyl portion of choice (m) are optionally substituted with        halogen, and        wherein the aryl of choice (o) and the heteroaryl of choice (p)        are optionally mono- or di-substituted with substituents        selected from halogen, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo        C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₆alkyl, —S(═O)_(o)C₃₋₆cycloalkyl, and CN;        R³ is selected from the group consisting of:    -   (a) hydrogen,    -   (b) halogen,    -   (c) CN,    -   (d) CF₃,    -   (e) —C₁₋₆alkyl,    -   (f) —C₁₋₆alkyl-C(═O)OH,    -   (g) —O—(R⁷),    -   (h) —S(═O)_(o)R⁷,    -   (i) —N(R⁷)(R⁸),    -   (j) —N(R⁷)—C(═O)—(R⁸),    -   (k) —N(R⁷)—C(═O)—O—(R⁸),    -   (l) —N(R⁷)S(═O)₂(R⁸),    -   (m) —C₃₋₆-cycloalkyl,    -   (n) —C(═O)(R⁷),    -   (o) aryl,    -   (p) heteroaryl,    -   (q) —OC(═O)N(R⁷)(R⁸),    -   (r) —S(═O)₂N(R⁷)(R⁸),    -   (s) —C(═O)N(R⁷)(R⁸),    -   (t) —C(R⁷)(R⁸)OH,    -   (u) —NHC(═O)—N(R⁷)(R⁸),    -   (v) —C₃₋₆cycloalkyl-COOH,    -   (w) heterocycle, and    -   (x) —C₁₋₆alkylC(═O)—N(R⁷)(R⁸),        wherein the alkyl portion of choices (e), (f) and (x), and the        cycloalkyl portion of choices (m) and (v) are optionally        substituted with halogen or hydroxyl, and        wherein the aryl of choice (o), the heteroaryl of choice (p),        and the heterocycle of choice (w) are optionally mono- or        di-substituted with substituents selected from halogen, nitro,        C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl), —NH(C₃₋₆cycloalkyl),        —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂, —S(═O)_(o)C₁₋₆alkyl,        —S(═O)_(o)C₃₋₆cycloalkyl, hydroxyl and CN;        R⁴ and R^(4′) are each independently selected from the group        consisting of:    -   (a) hydrogen,    -   (b) —N(R⁷)(R⁸),    -   (c) —N(R⁷)S(═O)₂R⁸,    -   (d) —N(R⁷)—C(═O)R⁸,    -   (e) —N(R′)C(═O)OR₈,    -   (f) —S(═O)_(o)R⁷,    -   (g) —S(═O)₂N(R⁷)(R⁸),    -   (h) —C(═O)R⁷,    -   (i) —C(═O)N(R⁷)(R⁸),    -   (j) —OC(═O)N(R⁷)(R⁸),    -   (k) —O—R⁷,    -   (l) —C(R⁷)(R⁸)OH,    -   (m) —C₁₋₄alkyl-C(═O)NHS(═O)₂R⁷,    -   (n) —C₁₋₄alkyl-S(═O)₂NHC(═O)R⁷,    -   (o) —C₁₋₄alkyl-C(═O)—N(R⁷)(R⁸),    -   (p) —C₁₋₄alkyl-N(R⁷)C(═O)(R⁸),    -   (q) —C₁₋₄alkyl-N(R⁷) S(═O)₂(R⁸),    -   (r) —C₁₋₄alkyl-S(═O)₂N(R⁷)(R⁸),    -   (s) —C₁₋₄alkyl-N(R⁷)C(═O)O(R⁸)    -   (t) —C₁₋₄alkyl-O—C(═O)N(R⁷)(R⁸)    -   (u) —C₁₋₄alkyl-C(═O)(R⁷),    -   (v) —C₁₋₄alkyl-C(R⁷)(R⁸)OH,    -   (w) —C₁₋₄alkyl-O(R⁷),    -   (x) —C₁₋₆alkyl-C(═O)OH,    -   (y) —C₂₋₆alkenyl-C(═O)OH,    -   (z) —C₃₋₆cycloalkyl-C(═O)OH,    -   (aa) —C₃₋₆cycloalkyl-C(═O)NHS(═O)₂R⁷,    -   (bb) —C₃₋₆cycloalkyl-S(═O)₂NHC(═O)R⁷,    -   (cc) —C₃₋₆cycloalkyl-C(═O)—N(R⁷)(R⁸),    -   (dd) —C₃₋₆cycloalkyl-N(R⁷)C(═O)(R⁸),    -   (ee) —C₃₋₆cycloalkyl-N(R⁷)S(═O)₂(R⁸),    -   (ff) —C₃₋₆cycloalkyl-S(═O)₂N(R⁷)(R⁸),    -   (gg) —C₃₋₆cycloalkyl-N(R⁷)C(═O)O(R⁸),    -   (jj) —C₃₋₆cycloalkyl-C(R⁷)(R⁸)OH,    -   (kk) —C₃₋₆cycloalkyl-O(R⁷),    -   (ll) —C(═O)OH,    -   (mm) aryl,    -   (nn) heteroaryl,    -   (oo) —C(═O)N(R⁷)S(═O)₂(R⁸),    -   (pp) —S(═O)₂N(R⁷)C(═O)(R⁸),    -   (qq) —NHS(═O)₂N(R⁷)(R⁸),    -   (rr) —NHC(═O)N(R⁷)(R⁸),    -   (ss) —CH(OH)—C(═O)—N(R⁷)(R⁸),    -   (tt) —C(═O)—C(═O)—N(R⁷)(R⁸),    -   (uu) —C₃₋₆-cycloalkyl,    -   (vv) —CF₃,    -   (ww) —C₁₋₆alkyl N(R⁷)(R⁸),    -   (xx)-heterocycle,    -   (yy) —C₁₋₆alkyl,    -   (zz) halogen, and    -   (aaa) —O—C₁₋₆alkyl-N(R⁷)(R⁸),        wherein the alkyl portion of choices (m), (n), (o), (p), (q),        (r), (s), (t), (u), (v), (w), (x), (ww), (yy) and (aaa), the        alkenyl portion of choice (y), and the cycloalkyl portion of        choices (z), (aa), (bb), (cc), (dd), (ee), (ff), (gg), (hh),        (ii), (jj), (kk) and (uu), are optionally mono- or        di-substituted with halogen, CN, aryl, C₁₋₆alkyl, halo        C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, or C₃₋₆cycloalkoxy, and        wherein the aryl of choice (mm), the heteroaryl of choice (nn),        and the heterocycle of choice (xx) are optionally mono- or        di-substituted with substituents selected from halogen, nitro,        C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl), —NH(C₃₋₆cycloalkyl),        —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂, —S(═O)_(o)C₁₋₆alkyl,        —S(═O)_(o)C₃₋₆cycloalkyl, hydroxyl and CN, or wherein R³ and R⁴        or R⁴ and R^(4′) are joined together to form a 5- or 6-membered        heterocyclic ring, said ring having one heteroatom selected from        O and N, wherein said ring is optionally substituted with        —C(═O)OH, or —C₁₋₆alkyl-C(═O)OH, with the proviso that at least        one of R³, R⁴ and R^(4′) is other than hydrogen; R⁵ is selected        from the group consisting of:    -   (a) hydrogen,    -   (b) —C₁₋₆alkyl,    -   (c) —C₁₋₄alkyl(R⁷),    -   (d) aryl,    -   (e) heteroaryl,    -   (f) —C₃₋₆cycloalkyl,    -   (g) —C₃₋₆cycloalkyl(R⁷),    -   (h) —C₃₋₆cycloalkyl-O(R⁷),    -   (i) —C₁₋₄alkyl-C₃₋₆cycloalkyl,    -   (j) —C₁₋₆alkoxy, and    -   (k) —C₃₋₆cycloalkoxy,        wherein the alkyl portion of choices (b), (c), (i) and (j), the        cycloalkyl portion of choices (f), (g), (h), (i) and (k) are        optionally substituted with halogen or C₁₋₄alkyl, and        wherein the aryl of choice (d) and the heteroaryl of choice (e),        are optionally mono- or di-substituted with substituents        selected from halogen, nitro, C₁₋₆alkyl, CF₃, C₁₋₆alkoxy, halo        C₁₋₆alkyl, aryl, heteroaryl, C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy,        and CN;        R⁶ is selected from the group consisting of:    -   (a) hydrogen,    -   (b) —C₁₋₆alkyl,    -   (c) —C₁₋₆alkylaryl,    -   (d) —C₁₋₆alkylheteroaryl,    -   (e) —S(═O)_(o)C₁₋₆alkyl(R⁷),    -   (f) —C(═O)C₁₋₆alkyl(R⁷),    -   (g) —C₃₋₆-cycloalkyl,    -   (h) aryl,    -   (i) hetereoaryl,    -   (j) —C(═O)C₃₋₆cycloalkyl(R⁷),    -   (k) —S(═O)_(o)C₃₋₆cycloalkyl(R⁷), and    -   (l) —C₁₋₆alkyl(R⁷),        wherein the alkyl portion of choices (b), (c), (d), (e), (f),        and (l) and the cycloalkyl portion of choices (g), (j), and (k),        are optionally substituted with halogen or C₁₋₄alkyl, and        wherein the aryl portion of choices (c) and (h), and the        heteroaryl portion of choices (d) and (i), are optionally mono-        or di-substituted with substituents selected from halogen,        nitro, —CF₃, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, aryl, heteroaryl, heterocycle        optionally substituted with halogen, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₆alkyl, S(═)C₃₋₆cycloalkyl, and CN;        R⁷ and R⁸ are each independently selected from the following:    -   (a) hydrogen,    -   (b) —C₁ alkyl,    -   (c) —C₃₋₆cycloalkyl,    -   (d)-aryl,    -   (e)-heteroaryl,    -   (f) —C₁₋₆alkylaryl,    -   (g) —C₁₋₆alkylheteroaryl,    -   (h) —C(═O)C₁₋₆alkyl,    -   (i) —S(═O)_(o)-aryl,    -   (j) —C₁₋₆alkyl-C₃₋₆cycloalkyl, and    -   (k) CF₃,        wherein the alkyl of choices (b), (f), (g), (h), and (j), and        the cycloalkyl of choices (c) and (j), are each optionally        mono-, di- or tri-substituted with halogen, and        wherein the aryl portion of choices (d), (f) and (i), and the        heteroaryl portion of choices (e) and (g), are each optionally        mono- or di-substituted with substituents selected from halogen,        —C(═O)OH, —CF₃, —NHC(═O)CH₃, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo        C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, —NH(C₁₋₃alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₃alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₄alkyl, S(═O)_(o)C₃₋₆cycloalkyl, aryl, heteroaryl,        hydroxyl, and CN;        R⁹ and R¹⁰ are each independently selected from the following    -   (a) hydrogen,    -   (b) —C₁₋₆alkyl,    -   (c) —C₃₋₆-cycloalkyl,    -   (d) halogen,    -   (e) —OC₃₋₆cycloalkyl,    -   (f) CF₃, and    -   (g) —C₁₋₆alkoxy,        wherein the alkyl portion of choice (b) and the cycloalkyl        portion of choices (c) and (e), are each optionally mono-, di-        or tri-substituted with halogen. In the alternative, choice (g)        of R⁹ and R¹⁰ may also be mono-, di- or tri-substituted with        halogen.

Within this aspect there is a genus wherein:

X is selected from the group consisting of —(CH₂)_(m)—, and—(CH₂)_(m)—O—(CH₂)_(n)—, optionally mono- or di-substituted withhalogen, where m+n is 2, 3 or 4.

Within this genus there is a sub-genus wherein:

X is selected from —CH₂CH₂CH₂—, or —CF₂CH₂CH₂—.

Within this aspect there is an alternative genus wherein:

X is selected from the group consisting of —(CH₂)_(m)—, and—(CH₂)_(m)—O—(CH₂)_(n)—, optionally mono- or di-substituted withhalogen, where m+n is 1, 2, 3 or 4.

Within this alternative genus there is a sub-genus wherein:

X is selected from —CH₂CH₂CH₂—, —CF₂CH₂CH₂—, or —OCH₂—.

Within this aspect there is a genus wherein:

A1 is a substituted phenyl or substituted pyridine.

Within this genus there is a sub-genus wherein:

A2 is A2a.

Within this sub-genus there is a class wherein:

A2a is a substituted phenyl, substituted pyrimidine, substitutedpyrazine, or substituted pyridine.

Within this aspect these is a genus wherein:

Y is O.

Within this aspect there is a genus wherein:

R¹ and R² are each independently selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) halogen,    -   (c) CN,    -   (d) CF₃,    -   (e) —C₁₋₆alkyl,    -   (f) —O—(R⁷),    -   (g) —C₃₋₆-cycloalkyl, and    -   (h) —N(R⁷)(R⁸),        wherein the alkyl portion of choice (e) and the cycloalkyl        portion of choice (g) are optionally substituted with halogen.

Within this genus there is a sub-genus wherein:

R¹ and R² are each independently selected from:

-   -   (a) hydrogen,    -   (b) halogen,    -   (c) CF₃,    -   (d) —C₁₋₆alkyl, and    -   (e) —O—(R⁷),        wherein the alkyl portion of choice (d) is optionally        substituted with halogen.

Within this sub-genus there is a class wherein R¹ and R² are eachhydrogen.

Within this aspect there is a genus wherein:

R³ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) halogen,    -   (c) CF₃,    -   (d) —C₁₋₆alkyl,    -   (e) —O—(R⁷),    -   (f) —S(═O)_(o)R⁷,    -   (g) —C₃₋₆-cycloalkyl,    -   (h) aryl,    -   (i) heteroaryl,    -   (j) —S(═O)₂N(R⁷)(R⁸),    -   (k) —C(R⁷)(R⁸)OH,    -   (l) heterocycle, and    -   (m) —N(R⁷)S(═O)₂(R⁸),        wherein the alkyl portion of choice (d) and the cycloalkyl        portion of choice (g) are optionally substituted with halogen or        hydroxyl, and        wherein the aryl of choice (h), the heteroaryl of choice (i),        and the heterocycle of choice (l) are optionally mono- or        di-substituted with substituents selected from halogen, nitro,        C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl), —NH(C₃₋₆cycloalkyl),        —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂, —S(═O)_(o)C₁₋₆alkyl,        —S(═O)_(o)C₃₋₆cycloalkyl, hydroxyl and CN.

Within this genus there is a sub-genus wherein:

R³ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) —O—(R⁷),    -   (c) —N(R⁷)S(═O)₂(R⁸), and    -   (d) —C₁₋₆-alkyl,        wherein the alkyl portion of choice (d) is optionally        substituted with halogen or hydroxyl.

Within this aspect there is a genus wherein:

R⁴ and R^(4′) are each independently selected from the group consistingof:

-   -   (a) hydrogen,    -   (b) —N(R⁷)S(═O)₂R⁸,    -   (c) —N(R⁷)—C(═O)R⁸,    -   (d) —S(═O)_(o)R⁷,    -   (e) —S(═O)₂N(R⁷)(R⁸),    -   (f) —C(═O)N(R⁷)(R⁸),    -   (g) —O—(R⁷),    -   (h) —C(R⁷)(R⁸)OH,    -   (i) —C₁₋₄alkyl-C(═O)NHS(═O)₂R⁷,    -   (j) —C₁₋₄alkyl-S(═O)₂NHC(═O)R⁷,    -   (k) —C₁₋₄alkyl —C(═O)—N(R⁷)(R⁸),    -   (l) —C₁₋₄alkyl-N(R⁷)C(═O)(R⁸),    -   (m) —C₁₋₄alkyl —N(R⁷) S(═O)₂(R⁸),    -   (n) —C₁₋₄alkyl —S(═O)₂N(R⁷)(R⁸),    -   (o) —C₁₋₄alkyl —C(R⁷)(R⁸)OH,    -   (p) —C₁₋₄alkyl-O(R⁷),    -   (q) —C₁₋₆alkyl-C(═O)OH,    -   (r) —C₂₋₆alkenyl-C(═O)OH,    -   (s) —C₃₋₆cycloalkyl-C(═O)OH,    -   (t) —C₃₋₆cycloalkyl-C(═O)NHS(═O)₂R⁷,    -   (u) —C₃₋₆cycloalkyl-S(═O)₂NHC(═O)R⁷,    -   (v) —C₃₋₆cycloalkyl-C(═O)—N(R⁷)(R⁸),    -   (w) —C₃₋₆-cycloalkyl-N(R⁷)S(═O)₂(R⁸),    -   (x) —C₃₋₆cycloalkyl-S(═O)₂N(R⁷)(R⁸),    -   (y) —C₃₋₆cycloalkyl-N(R⁷)C(═O)O(R⁸),    -   (z) —C₃₋₆cycloalkyl 1-C(R⁷)(R⁸)OH,    -   (aa) —C₃₋₆cycloalkyl-O(R⁷),    -   (bb) —C(═O)OH,    -   (cc) aryl,    -   (dd) heteroaryl,    -   (ee) —C(═O)N(R⁷)S(═O)₂(R⁸),    -   (ff) —S(═O)₂N(R⁷)C(═O)(R⁸),    -   (gg) —NHS(═O)₂N(R⁷)(R⁸),    -   (hh) —NHC(═O)N(R⁷)(R⁸),    -   (ii) —C₃₋₆cycloalkyl,    -   (jj) CF₃,    -   (kk) heterocycle,    -   (ll) —C₁₋₆-alkyl, and    -   (mm) halogen,        wherein the alkyl portion of choices (i), (j), (k), (l), (m),        (n), (o), (p), (q), and (ll), the alkenyl portion of choice (r),        and the cycloalkyl portion of choices (s), (t), (u), (v), (w),        (x), (y), (z), and (aa) are optionally mono- or di-substituted        with halogen, CN, aryl, C₁₋₆alkyl, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₁₋₆alkoxy, or C₃₋₆cycloalkoxy and,        wherein the aryl of choice (cc), the heteroaryl of choice (dd),        and the heterocycle of choice (kk) are optionally mono- or        di-substituted with substituents selected from halogen,        hydroxyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₆alkyl, —S(═O)_(o)C₃₋₆cycloalkyl, and CN. In the        alternative, choice (ii) of R⁴ and R^(4′) may also be mono- or        di-substituted with halogen, CN, aryl, C₁₋₆alkyl, halo        C₁₋₆alkyl, C₃₋₆-cycloalkyl, C₁₋₆alkoxy, or C₃₋₆cycloalkoxy        halogen.

Within this genus there is a sub-genus wherein:

R⁴ and R^(4′) are each independently selected from the group consistingof:

-   -   (a) hydrogen,    -   (b) —N(R⁷)S(═O)₂R⁸,    -   (c) —N(R⁷)—C(═O)R⁸,    -   (d) —O—(R⁷),    -   (e) —C(R⁷)(R⁸)OH,    -   (f) —C₁₋₄alkyl-S(═O)₂NHC(═O)R⁷,    -   (g) —C₁₋₄alkyl-N(R⁷) S(═O)₂(R⁸),    -   (h) —C₁₋₄alkyl —S(═O)₂N(R⁷)(R⁸),    -   (i) —C₁₋₄alkyl-O(R⁷),    -   (j) —C₁₋₆ alkyl-C(═O)OH,    -   (k) —C₃₋₆cycloalkyl-C(═O)OH,    -   (l) —C₃₋₆cycloalky —N(R⁷)S(═O)₂(R⁸),    -   (m) —C₃₋₆cycloalkyl-S(═O)₂N(R⁷)(R⁸),    -   (n) —C₃₋₆cycloalkyl-O(R⁷),    -   (o) —C(═O)OH,    -   (p) —C(═O)N(R⁷) S(═O)₂(R⁸),    -   (q) —S(═O)₂N(R⁷)C(═O)(R⁸),    -   (r) —NHS(═O)₂N(R⁷)(R⁸),    -   (s) —C₃₋₆cycloalkyl,    -   (t) CF₃,    -   (u) heterocycle,    -   (v) —C₁₋₆alkyl, and    -   (w) halogen,        wherein the alkyl portion of choices (f), (g), (h), (i), (j),        and (v), and the cycloalkyl portion of choices (k), (l), (m),        (n), and (s), are optionally mono- or di-substituted with        halogen, CN, aryl, C₁₋₆alkyl, halo C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₁₋₆alkoxy, or C₃₋₆cycloalkoxy, and        wherein the heterocycle of choice (u) is optionally mono- or        di-substituted with substituents selected from halogen,        hydroxyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₆alkyl, —S(═O)_(o)C₃₋₆cycloalkyl and CN.

Within this sub-genus there is class wherein:

R⁴ and R^(4′) are each independently selected from the group consistingof:

-   -   (a) —C(R⁷)(R⁸)OH,    -   (b) —N(R⁷)S(═O)₂R⁸,    -   (c) —O—(R⁷),    -   (d) —C₁₋₆alkyl —C(═O)OH,    -   (e) —C(═O)OH,    -   (f) —NHS(═O)₂N(R⁷)(R⁸),    -   (g) —C₃₋₆cycloalkyl,    -   (h) CF₃,    -   (i) heterocycle,    -   (j) —C₁₋₆alkyl, and    -   (k) halogen,        wherein the alkyl portion of choices (d) and (j), and the        cycloalkyl portion of choice (g) are optionally mono- or        di-substituted with halogen, CN, aryl, C₁₋₆alkyl, halo        C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, or C₃₋₆cycloalkoxy, and        wherein the heterocycle of choice (i) is optionally mono- or        di-substituted with substituents selected from halogen,        hydroxyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₆alkyl, —S(═O)_(o)C₃₋₆cycloalkyl, and CN.

Within this aspect there is a genus wherein:

R⁵ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) —C₁₋₆alkyl,    -   (c) —C₁₋₄alkyl(R⁷),    -   (d) aryl,    -   (e) heteroaryl,    -   (f) —C₃₋₆cycloalkyl, and    -   (g) —C₁₋₄alkyl-C₃₋₆cycloalkyl,        wherein the alkyl portion of choices (b), (c), and (g), the        cycloalkyl portion of choices (f) and (g), are optionally        substituted with halogen or C₁₋₄alkyl, and        wherein the aryl of choice (d) and the heteroaryl of choice (e),        is optionally mono- or di-substituted with substituents selected        from halogen, nitro, C₁₋₆alkyl, CF₃, C₁₋₆alkoxy, halo C₁₋₆alkyl,        aryl, heteroaryl, C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, and CN.

Within this genus there is a sub-genus wherein

R⁵ is selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) —C₁₋₆alkyl, and    -   (c) —C₁₋₄alkyl(R⁷),        wherein the alkyl portion of choices (b) and (c) is optionally        substituted with halogen or C₁₋₄alkyl.

Within this aspect there is a genus wherein:

R⁶ is selected from the group consisting of:

-   -   (a) —C₁₋₆alkylaryl,    -   (b) —C₁₋₆alkylheteroaryl,    -   (c) —C₃₋₆-cycloalkyl,    -   (d) aryl,    -   (e) hetereoaryl, and    -   (f) —C₁₋₆alkyl(R⁷),        wherein the alkyl portion of choices (a), (b) and (f), and the        cycloalkyl portion of choice (c) are optionally substituted with        halogen or C₁₋₄alkyl, and        wherein the aryl portion of choices (a) and (d), and the        heteroaryl portion of choices (b) and (e), are optionally mono-        or di-substituted with substituents selected from halogen,        nitro, CF₃, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, aryl, heteroaryl, heterocycle        optionally substituted with halogen, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₆alkyl, —S(═)C₃₋₆cycloalkyl, and CN.

Within this genus there is a sub-genus wherein:

R⁶ is selected from the group consisting of:

-   -   (a) —C₁₋₆alkylaryl,    -   (b) —C₁₋₆alkylheteroaryl, and    -   (c) —C₁₋₆alkyl(R⁷),        wherein the alkyl portion of choices (a), (b), and (c) is        optionally substituted with halogen or C₁₋₄alkyl, and        wherein the aryl portion of choice (a), and the heteroaryl        portion of choice (b), are optionally mono- or di-substituted        with substituents selected from halogen, nitro, CF₃, C₁₋₆alkyl,        C₁₋₆alkoxy, halo C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkoxy,        aryl, heteroaryl, heterocycle optionally substituted with        halogen, —NH(C₁₋₆alkyl), —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂,        —N(C₃₋₆cycloalkyl)₂, —S(═O)_(o)C₁₋₆alkyl,        —S(═O)_(o)C₃₋₆cycloalkyl, and CN.

Within this aspect there is a genus wherein:

R⁷ and R⁸ are each independently selected from the following:

-   -   (a) hydrogen,    -   (b) —C₁₋₆alkyl,    -   (c) —C₃₋₆-cycloalkyl,    -   (d) aryl,    -   (e) heteroaryl, and    -   (f) CF₃,        wherein the alkyl of choice (b) and the cycloalkyl of choice (c)        are optionally mono-, di- or tri-substituted with halogen, and        wherein the aryl of choice (d) and the heteroaryl of choice (e)        are optionally mono- or di-substituted with substituents        selected from halogen, —C(═O)OH, CF₃, —NHC(═O)—CH₃, nitro,        C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkoxy, —NH(C₁₋₃alkyl), —NH(C₃₋₆cycloalkyl),        —N(C₁₋₃alkyl)₂, —N(C₃₋₆cycloalkyl)₂, —S(═O)_(o)C₁₋₄alkyl,        —S(═O)_(o)C₃₋₆cycloalkyl, aryl, heteroaryl, hydroxyl, and CN.

Within this aspect there is a genus wherein:

R⁹ and R¹⁰ are each independently

-   -   (a) hydrogen,    -   (b) —C₁₋₆alkyl,    -   (c) halogen,    -   (d) CF₃, and    -   (e) —C₁₋₆alkoxy,        wherein the alkyl of choice (b) is optionally mono-, di- or        tri-substituted with halogen. In the alternative, the alkyl        portion of choice (e) of R⁹ and R¹⁰ may also be mono-, di- or        tri-substituted with halogen.

Within this aspect there is a genus wherein:

X is selected from the group consisting of —(CH₂)_(m)—, and—(CH₂)_(m)—O—(CH₂)_(n)—, optionally mono or di-substituted with halogen,where m+n is 2, 3 or 4;

Y is O;

A1 is a substituted phenyl or substituted pyridine;

A2 is A2a;

R¹ and R² are each independently selected from the group consisting of:

-   -   (a) hydrogen,    -   (b) halogen,    -   (c) CN,    -   (d) CF₃,    -   (e) —C₁₋₆alkyl,    -   (f) —O—(R⁷),    -   (g) —C₃₋₆cycloalkyl, and    -   (h) —N(R⁷)(R⁸),        wherein the alkyl portion of choice (e) and the cycloalkyl        portion of choice (g) are optionally substituted with halogen;        R³ is selected from the group consisting of:    -   (a) hydrogen,    -   (b) halogen,    -   (c) CF₃,    -   (d) —C₁₋₆alkyl,    -   (e) —O—(R⁷),    -   (f) —S(═O)_(o)R⁷,    -   (g) —C₃₋₆-cycloalkyl,    -   (h) aryl,    -   (i) heteroaryl,    -   (j) —S(═O)₂N(R⁷)(R⁸),    -   (k) —C(R⁷)(R⁸)OH,    -   (l) heterocycle, and    -   (m) —N(R⁷)S(═O)₂(R⁸),        wherein the alkyl portion of choice (d) and the cycloalkyl        portion of choice (g) are optionally substituted with halogen or        hydroxyl, and        wherein the aryl of choice (h), the heteroaryl of choice (i),        and the heterocycle of choice (l) are optionally mono- or        di-substituted with substituents selected from halogen, nitro,        C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl), —NH(C₃₋₆cycloalkyl),        —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂, —S(═O)_(o)C₁₋₆alkyl,        —S(═O)_(o)C₃₋₆cycloalkyl, hydroxyl and CN;        R⁴ and R^(4′) are each independently selected from the group        consisting of:    -   (a) hydrogen,    -   (b) —N(R⁷)S(═O)₂R⁸,    -   (c) —N(R⁷)—C(═O)R⁸,    -   (d) —S(═O)_(o)R⁷,    -   (e) —S(═O)₂N(R⁷)(R⁸),    -   (f) —C(═O)N(R⁷)(R⁸),    -   (g) —O—(R⁷),    -   (h) —C(R⁷)(R⁸)OH,    -   (i) —C₁₋₄alkyl-C(═O)NHS(═O)₂R⁷,    -   (j) —C₁₋₄alkyl-S(═O)₂NHC(═O)R⁷,    -   (k) —C₁₋₄alkyl-C(═O)—N(R⁷)(R⁸),    -   (l) —C₁₋₄alkyl-N(R⁷)C(═O)(R⁸),    -   (m) —C₁₋₄alkyl-N(R⁷) S(═O)₂(R⁸),    -   (n) —C₁₋₄alkyl-S(═O)₂N(R⁷)(R⁸),    -   (o) —C₁₋₄alkyl —C(R⁷)(R⁸)OH,    -   (p) —C₁₋₄alkyl-O(R⁷),    -   (q) —C₁₋₆alkyl-C(═O)OH,    -   (r) —C₂₋₆alkenyl-C(═O)OH,    -   (s) —C₃₋₆cycloalkyl-C(═O)OH,    -   (t) —C₃₋₆cycloalkyl-C(═O)NHS(═O)₂R⁷,    -   (u) —C₃₋₆cycloalkyl-S(═O)₂NHC(═O)R⁷,    -   (v) —C₃₋₆cycloalkyl-C(═O)—N(R⁷)(R⁸),    -   (w) —C₃₋₆-cycloalkyl-N(R⁷)S(═O)₂(R⁸),    -   (x) —C₃₋₆cycloalkyl-S(═O)₂N(R⁷)(R⁸),    -   (y) —C₃₋₆cycloalkyl-N(R⁷)C(═O)O(R⁸),    -   (z) —C₃₋₆cycloalkyl 1-C(R⁷)(R⁸)OH,    -   (aa) —C₃₋₆cycloalkyl-O(R⁷),    -   (bb) —C(═O)OH,    -   (cc) aryl,    -   (dd) heteroaryl,    -   (ee) —C(═O)N(R⁷)S(═O)₂(R⁸),    -   (ff) —S(═O)₂N(R⁷)C(═O)(R⁸),    -   (gg) —NHS(═O)₂N(R⁷)(R⁸),    -   (hh) —NHC(═O)N(R⁷)(R⁸),    -   (ii) —C₃₋₆cycloalkyl,    -   (jj) CF₃,    -   (kk) heterocycle,    -   (ll) —C₁₋₆alkyl, and    -   (mm) halogen,        wherein the alkyl portion of choices (i), (j), (k), (l), (m),        (n), (o), (p), (q), and (ll), the alkenyl portion of choice (r),        and the cycloalkyl portion of choices (s), (t), (u), (v), (w),        (x), (y), (z), and (aa) are optionally mono- or di-substituted        with halogen, CN, aryl, C₁₋₆alkyl, halo C₁₋₆alkyl,        C₃₋₆-cycloalkyl, C₁₋₆alkoxy, or C₃₋₆cycloalkoxy and,        wherein the aryl of choice (cc), the heteroaryl of choice (dd),        and the heterocycle of choice (kk) are optionally mono- or        di-substituted with substituents selected from halogen,        hydroxyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C-alkyl, —S(═O)_(o)C₃₋₆cycloalkyl, and CN;        R⁵ is selected from the group consisting of:    -   (a) hydrogen,    -   (b) —C₁₋₆alkyl,    -   (c) —C₁₋₄alkyl(R⁷),    -   (d) aryl,    -   (e) heteroaryl,    -   (f) —C₃₋₆cycloalkyl, and    -   (g) —C₁₋₄alkyl-C₃₋₆cycloalkyl,        wherein the alkyl portion of choices (b), (c) and (g), the        cycloalkyl portion of choices (f) and (g), are optionally        substituted with halogen or C₁₋₄alkyl, and        wherein the aryl of choice (d) and the heteroaryl of choice (e),        are optionally mono- or di-substituted with substituents        selected from halogen, nitro, C₁₋₆alkyl, CF₃, C₁₋₆alkoxy, halo        C₁₋₆alkyl, aryl, heteroaryl, C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy,        and CN;        R⁶ is selected from the group consisting of:    -   (a) —C₁₋₆alkylaryl,    -   (b) —C₁₋₆alkylheteroaryl,    -   (c) C₃₋₆cycloalkyl,    -   (d) aryl,    -   (e) hetereoaryl, and    -   (f) —C₁₋₆alkyl(R⁷),        wherein the alkyl portion of choices (a), (b) and (f), and the        cycloalkyl portion of choice (c) are optionally substituted with        halogen or C₁₋₄alkyl, and        wherein the aryl portion of choices (a) and (d), and the        heteroaryl portion of choices (b) and (e), are optionally mono-        or di-substituted with substituents selected from halogen,        nitro, CF₃, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, aryl, heteroaryl, heterocycle        optionally substituted with halogen, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₆alkyl, —S(═)C₃₋₆cycloalkyl, and CN;        R⁷ and R⁸ are each independently selected from the following:    -   (a) hydrogen,    -   (b) C₁₋₆ alkyl,    -   (c) C₃₋₆cycloalkyl,    -   (d) aryl,    -   (e) heteroaryl, and    -   (f) CF₃,        wherein the alkyl of choice (b) and the cycloalkyl of choice (c)        are optionally mono-, di- or tri-substituted with halo, and        wherein the aryl of choice (d) and the heteroaryl of choice (e)        are optionally mono- or di-substituted with substituents        selected from halogen, —C(═O)OH, CF₃, —NHC(═O)—CH₃, nitro,        C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, C₃₋₆cycloalkyl,        C₃₋₆cycloalkoxy, —NH(C₁₋₃alkyl), —NH(C₃₋₆cycloalkyl),        —N(C₁₋₃alkyl)₂, —N(C₃₋₆cycloalkyl)₂, —S(═O)_(o)C₁₋₄alkyl,        —S(═O)_(o)C₃₋₆cycloalkyl, aryl, heteroaryl, hydroxyl, and CN;        and        R⁹ and R¹⁰ are each independently    -   (a) hydrogen,    -   (b) —C₁₋₆alkyl,    -   (c) halogen,    -   (d) CF₃, and    -   (e) C₁₋₆alkoxy,        wherein the alkyl of choice (b) is optionally mono-, di- or        tri-substituted with halogen. In the alternative aspect,        choice (ii) of R⁴ and R^(4′) may also be mono- or di-substituted        with halogen, CN, aryl, C₁₋₆alkyl, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₁₋₆-alkoxy, or C₃₋₆cycloalkoxy halogen; and the        alkyl portion of choice (e) is optionally mono-, di- or        tri-substituted with halogen and choice (e) of R⁹ and R¹⁰ may        also be mono-, di- or tri-substituted with halogen

Within this genus there is a sub-genus wherein:

A2 is A2a, and A2a is a substituted phenyl, substituted pyrimidine,substituted pyrazine, or substituted pyridine;R¹ and R² are each independently selected from:

-   -   (a) hydrogen,    -   (b) halogen,    -   (c) CF₃,    -   (d) C₁₋₆alkyl, and    -   (e) —O—(R⁷),        wherein the alkyl portion of choice (d) is optionally        substituted with halogen;        R³ is selected from the group consisting of:    -   (a) hydrogen,    -   (b) —O—(R⁷),    -   (c) —N(R⁷)S(═O)₂(R⁸), and    -   (d) —C₁₋₆-alkyl,        wherein the alkyl portion of choice (d) is optionally        substituted with halogen or hydroxyl;        R⁴ and R^(4′) are each independently selected from the group        consisting of:    -   (a) hydrogen,    -   (b) —N(R⁷)S(═O)₂R⁸,    -   (c) —N(R⁷)—C(═O)R⁸,    -   (d) —O—(R⁷),    -   (e) —C(R⁷)(R⁸)OH,    -   (f) —C₁₋₄alkyl-S(═O)₂NHC(═O)R⁷,    -   (g) —C₁₋₄alkyl-N(R⁷) S(═O)₂(R⁸),    -   (h) —C₁₋₄alkyl-S(═O)₂N(R⁷)(R⁸),    -   (i) —C₁₋₄alkyl-O(R⁷),    -   (j) —C₁₋₆-alkyl-C(═O)OH,    -   (k) —C₃₋₆cycloalkyl-C(═O)OH,    -   (l) —C₃₋₆cycloalkyl-N(R⁷)S(═O)₂(R⁸),    -   (m) —C₃₋₆cycloalkyl-S(═O)₂N(R⁷)(R⁸),    -   (n) —C₃₋₆cycloalkyl-O(R⁷),    -   (o) —C(═O)OH,    -   (p) —C(═O)N(R⁷) S(═O)₂(R⁸),    -   (q) —S(═O)₂N(R⁷)C(═O)(R⁸),    -   (r) —NHS(═O)₂N(R⁷)(R⁸),    -   (s) —C₃₋₆cycloalkyl,    -   (t) CF₃,    -   (u) heterocycle,    -   (v) —C₁₋₆alkyl, and    -   (w) halogen,        wherein the alkyl portion of choices (f), (g), (h), (i), (j),        and (v), and the cycloalkyl portion of choices (k), (l), (m),        (n), and (s), are optionally mono- or di-substituted with        halogen, CN, aryl, C₁₋₆alkyl, halo C₁₋₆alkyl, C₃₋₆cycloalkyl,        C₁₋₆alkoxy, or C₃₋₆cycloalkoxy, and        wherein the heterocycle of choice (u) is optionally mono- or        di-substituted with substituents selected from halogen,        hydroxyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₆alkyl, —S(═O)_(o)C₃₋₆cycloalkyl and CN;        R⁵ is selected from the group consisting of:    -   (a) hydrogen,    -   (b) —C₁₋₆alkyl, and    -   (c) —C₁₋₄alkyl(R⁷),        wherein the alkyl portion of choices (b) and (c) is optionally        substituted with halogen or C₁₋₄alkyl;        R⁶ is selected from the group consisting of:    -   (a) —C₁₋₆alkylaryl,    -   (b) —C₁₋₆alkylheteroaryl, and    -   (c) —C₁₋₆alkyl(R⁷),        wherein the alkyl portion of choices (a), (b), and (c) is        optionally substituted with halogen or C₁₋₄alkyl, and        wherein the aryl portion of choice (a), and the heteroaryl        portion of choice (b), are optionally mono- or di-substituted        with substituents selected from halogen, nitro, CF₃, C₁₋₆alkyl,        C₁₋₆alkoxy, halo C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy,        aryl, heteroaryl, heterocycle optionally substituted with        halogen, —NH(C₁₋₆alkyl), —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂,        —N(C₃₋₆cycloalkyl)₂, —S(═O)_(o)C₁₋₆alkyl,        —S(═O)_(o)C₃₋₆cycloalkyl, and CN.

Within this sub-genus there is a class wherein:

R⁴ and R^(4′) are each independently selected from the group consistingof:

-   -   (a) —C(R⁷)(R⁸)OH,    -   (b) —N(R⁷)S(═O)₂R⁸,    -   (c) —O—(R⁷),    -   (d) —C₁₋₆alkyl-C(═O)OH,    -   (e) —C(═O)OH,    -   (f) —NHS(═O)₂N(R⁷)(R⁸),    -   (g) C₃₋₆cycloalkyl,    -   (h) CF₃,    -   (i) heterocycle,    -   (j) —C₁₋₆alkyl, and    -   (k) halogen,        wherein the alkyl portion of choices (d) and (j), and the        cycloalkyl portion of choice (g) are optionally mono- or        di-substituted with halo, CN, aryl, C₁₋₆alkyl, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₁₋₆alkoxy, or C₃₋₆cycloalkoxy, and        wherein the heterocycle of choice (i) is optionally mono- or        di-substituted with substituents selected from halogen,        hydroxyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl,        C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, —NH(C₁₋₆alkyl),        —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂,        —S(═O)_(o)C₁₋₆alkyl, —S(═O)_(o)C₃₋₆cycloalkyl, and CN.

Within this class there is a sub-class wherein of Formula 1a

or a pharmaceutically acceptable salt thereof.

Within this sub-class there is a sub-sub-class wherein of Formula 1b

or a pharmaceutically acceptable salt thereof.

In some embodiments, R³ is not hydrogen. In some embodiments, R⁴ is nothydrogen. In some embodiments, R³ is not hydrogen; and R⁴ is nothydrogen.

In one aspect, described herein are the following compounds:

-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)acetic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-yl)acetic    acid,-   3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-carboxylic    acid,-   3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-carboxylic    acid,-   1-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)cyclopropanecarboxylic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic    acid,-   1-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)cyclopropanecarboxylic    acid,-   1-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-yl)cyclopropanecarboxylic    acid,-   3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methoxy-[1,1′-biphenyl]-3-carboxylic    acid,-   3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-carboxylic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-propoxy-[1,1′-biphenyl]-3-yl)acetic    acid,-   N-(6-(3-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)phenyl)pyridin-3-yl)benzenesulfonamide,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,    5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methoxy-[1,1′-biphenyl]-3-yl)acetic    acid,-   1-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methy-1-[1,1′-biphenyl]-3-yl)cyclopropanecarboxylic    acid,-   2-(4-(benzyloxy)-3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)acetic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-(cyclopropylmethoxy)-[1,1′-biphenyl]-3-yl)acetic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-fluoro-[1,1′-biphenyl]-3-yl)acetic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-6-ethoxy-[1,1′-biphenyl]-3-yl)acetic    acid,-   3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-propoxy-[1,1′-biphenyl]-3-carboxylic    acid,-   N-((3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-ox-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)methyl)benzenesulfonamide,-   3-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methoxy-[1,1′-biphenyl]-3-yl)propanoic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,1-difluoropropyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetic    acid,-   N-(6-(3-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,1-difluoropropyl)phenyl)pyridin-3-yl)benzenesulfonamide,-   2-(5-(6-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyridin-2-yl)-2-methoxyphenyl)acetic    acid,-   3-(3-(3′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one,-   2-(5-(4-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyrimidin-2-yl)-2-ethoxyphenyl)acetic    acid,-   2-(5-(6-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyrimidin-4-yl)-2-ethoxyphenyl)acetic    acid,-   (3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-methoxy-[1,1′-biphenyl]-4-yl)acetic    acid,-   (3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)propyl)-3-ethoxy-[1,1′-biphenyl]-4-yl)acetic    acid,-   (3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-propoxy-[1,1′-biphenyl]-4-yl)acetic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-hydroxy-[1,1′-biphenyl]-4-yl)acetic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triaz-3-yl)propyl)-4-isopropoxy-[1,1′-biphenyl]-3-yl)acetic    acid,-   2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-3-yl)acetic    acid,-   or a pharmaceutically acceptable salt thereof.

In another aspect the invention is directed to a pharmaceuticalcomposition comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect the invention is directed to a method of treating acancer which is negatively impacted by diminution in its metabolism offatty acid, through the administration of a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof.

Within this aspect there is a genus wherein the cancer is selected fromprostate, breast, ovarian, liver, kidney, colon, pancreatic, humanchronic lymphocytic leukemia, and melanoma.

In another aspect the invention is directed to a method of treatingcancer involving the administration of a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof.

In another aspect the invention is directed to a method of preventingthe onset of and/or recurrence of acute and chronic myeloid leukemia, aswell as other cancers through the administration of a therapeuticallyeffective amount of a compound according to Claim 1, or apharmaceutically acceptable salt thereof.

Definitions

The term “patient” includes mammals such as mice, rats, cows, sheep,pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” refers to a saturated hydrocarbon chain that may be astraight chain or branched chain, containing the indicated number ofcarbon atoms. For example, C₁₋₆alkyl indicates that the group may havefrom 1 to 6 (inclusive) carbon atoms in it. Any atom can be optionallysubstituted, e.g., by one or more substitutents. Examples of alkylgroups include without limitation methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl and tert-butyl.

The term “haloalkyl” refers to an alkyl group, in which at least onehydrogen atom is replaced by halo. In some embodiments, more than onehydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) arereplaced by halo. In these embodiments, the hydrogen atoms can each bereplaced by the same halogen (e.g., fluoro) or the hydrogen atoms can bereplaced by a combination of different halogens (e.g., fluoro andchloro). “Haloalkyl” also includes alkyl moieties in which all hydrogenshave been replaced by halo (sometimes referred to herein asperhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). Any atomcan be optionally substituted, e.g., by one or more substituents.

As referred to herein, the term “alkoxy” refers to a group of formula—O(alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy,3-pentoxy, or hexyloxy. Likewise, the term “thioalkoxy” refers to agroup of formula —S(alkyl). The terms “haloalkoxy” and “halothioalkoxy”refer to —O(haloalkyl) and —S(haloalkyl), respectively. The term“sulfhydryl” refers to —SH.

The term “aralkyl” refers to an alkyl moiety in which an alkyl hydrogenatom is replaced by an aryl group. One of the carbons of the alkylmoiety serves as the point of attachment of the aralkyl group to anothermoiety. Any ring or chain atom can be optionally substituted e.g., byone or more substituents. Non-limiting examples of “aralkyl” includebenzyl, 2-phenylethyl, and 3-phenylpropyl groups.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining the indicated number of carbon atoms and having one or morecarbon-carbon double bonds. Any atom can be optionally substituted,e.g., by one or more substituents. Alkenyl groups can include, e.g.,vinyl, allyl, 1-butenyl, and 2-hexenyl.

The term “heterocycle” or “heterocyclic”, as used herein except wherenoted, represents a stable 4-, 5-, 6- or 7-membered monocyclic- orstable 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered fused bicyclicheterocyclic ring system which comprises at least one non-aromatic (i.e.saturated or partially unsaturated) ring which consists of carbon atomsand from one to four heteroatoms selected from the group consisting ofN, O and S, wherein the nitrogen and sulfur heteroatoms may optionallybe oxidized, and wherein the nitrogen heteroatom may optionally bequaternized. In the case of a “heterocycle” which is a bicyclic group,the second ring may also be a non-aromatic ring which consists of carbonatoms and from one to four heteroatoms selected from the groupconsisting of N, O and S, as defined above, or the second ring may be abenzene ring, or a “cycloalkyl”, or a “cycloalkenyl”, as definedimmediately below. Examples of such heterocyclic groups include, but arenot limited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane,dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline,isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline,isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine,piperidine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline,tetrahydrofuran, tetrahydropyran, thiamorpholine, thiazoline,thiazolidine, thiomorpholine and N-oxides thereof.

The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic,tricyclic, or other polycyclic hydrocarbon groups. Any atom can beoptionally substituted, e.g., by one or more substituents. A ring carbonserves as the point of attachment of a cycloalkyl group to anothermoiety. Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl(bicycle[2.2.1]heptyl).

The term “cycloalkenyl” refers to partially unsaturated monocyclic,bicyclic, tricyclic, or other polycyclic hydrocarbon groups. A ringcarbon (e.g., saturated or unsaturated) is the point of attachment ofthe cycloalkenyl substituent. Any atom can be optionally substitutede.g., by one or more substituents. Cycloalkenyl moieties can include,e.g., cyclopentenyl, cyclohexenyl, cyclohexadienyl, or norbornenyl.

The term “cycloalkylene”, as used herein, refers to a divalentmonocyclic cycloalkyl group having the indicated number of ring atoms.

The term “heterocycloalkylene”, as used herein, refers to a divalentmonocyclic heterocyclyl group having the indicated number of ring atoms.

The term “aryl” as used herein, is intended to mean any stablemonocyclic or bicyclic carbon ring of up to 7 members in each ring,wherein at least one ring is aromatic. Examples of such aryl elementsinclude phenyl, naphthyl, tetrahydronaphthyl, indanyl, or biphenyl.

The term “heteroaryl”, as used herein except where noted, represents astable 5, 6 or 7-membered monocyclic- or stable 9 or 10-membered fusedbicyclic ring system which comprises at least one aromatic ring,—whichconsists of carbon atoms and from one to three heteroatoms selected fromthe group consisting of N, O and S wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. In the case of a “heteroaryl” which is abicyclic group, the second ring need not be aromatic and need notcomprise a heteroatom. Accordingly, “heteroaryl” includes, for example,a stable 5, 6 or 7-membered monocyclic aromatic ring consisting ofcarbon atoms and from one to four heteroatoms, as defined immediatelyabove, fused to a benzene ring, or fused to a “heterocycle”,“cycloalkyl”, or a “cycloalkenyl”, as defined above. Examples of suchheteroaryl groups include, but are not limited to, benzimidazole,benzisothiazole, benzisoxazole, benzofuran, isobenzofuran,benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline,cinnoline, furan, furazan, imidazole, indazole, indole, indolizine,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, andN-oxides thereof.

The term “acyl”, as used herein, refers to those groups derived from anorganic acid by removal of the hydroxy portion of the acid. Accordingly,acyl is meant to include, for example, acetyl, propionyl, butyryl,decanoyl, pivaloyl, benzoyl and the like.

Compound Forms and Salts

The compounds of this invention may contain one or more stereocentersand thus occur as racemates and racemic mixtures,enantiomerically-enriched mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures. The compounds of thisinvention may also be represented in multiple tautomeric forms, in suchinstances, the invention expressly includes all tautomeric forms of thecompounds described herein, even though only a single tautomeric formmay be represented. All such isomeric forms of such compounds areexpressly included in the present invention.

The compounds of this invention include the compounds themselves, aswell as their salts and their prodrugs, if applicable. A salt, forexample, can be formed between an anion and a positively chargedsubstituent (e.g., ammonium) on a compound described herein. Suitableanions include chloride, bromide, iodide, sulfate, nitrate, phosphate,citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, asalt can also be formed between a cation and a negatively chargedsubstituent (e.g., carboxylate) on a compound described herein. Suitablecations include sodium ion, potassium ion, magnesium ion, calcium ion,and an ammonium cation such as tetramethylammonium ion.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In one aspect of the invention the salts are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids.

When the compound of the present invention is acidic, salts may beprepared from pharmaceutically acceptable non-toxic bases, includinginorganic and organic bases. Such salts that may be prepared include alithium salt, sodium salt, potassium salt, magnesium salt, calcium salt,dicyclohexylamine salt, N-methyl-D-glucamine salt,tris(hydroxymethyl)methylamine salt, arginine salt, lysine salt, and thelike.

Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418;Journal of Pharmaceutical Science, 66, 2 (1977); and “PharmaceuticalSalts: Properties, Selection, and Use A Handbook; Wermuth, C. G. andStahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN3-906390-26-8] each of which is incorporated herein by reference intheir entireties.

The compounds may be radiolabeled with radioactive isotopes, such as forexample tritium, iodine-125 or carbon-14. All isotopic variations of thecompounds of the invention, whether radioactive or not, are intended tobe encompassed within the scope of the invention.

In some embodiments, hydrogen atoms of the compounds described hereinmay be replaced with deuterium atoms.

In some embodiments, compounds of Formula I are prepared as prodrugs.Prodrugs are generally drug precursors that, following administration toa subject and subsequent absorption, are converted to an active, or amore active species via some process, such as conversion by a metabolicpathway. Examples of prodrugs include C₁₋₆ alkyl esters of carboxylicacid groups, which, upon administration to a subject, are capable ofproviding active compounds.

Pharmaceutical Compositions

The term “pharmaceutically acceptable carrier” refers to a carrier oradjuvant that may be administered to a patient, together with a compoundof this invention, or a pharmaceutically acceptable salt thereof, andwhich does not destroy the pharmacological activity thereof and isnontoxic when administered in doses sufficient to deliver a therapeuticamount of the compound.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier. By “pharmaceuticallyacceptable” it is meant the carrier, diluent or excipient must becompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the terms “administrationof” or “administering a” compound shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient.

Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs,”ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds includeactive species produced upon introduction of compounds of this inventioninto the biological milieu.

The amount administered depends on the compound formulation, route ofadministration, etc. and is generally empirically determined in routinetrials, and variations will necessarily occur depending on the target,the host, and the route of administration, etc. Generally, the quantityof active compound in a unit dose of preparation may be varied oradjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg,according to the particular application. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired.

Uses

In one aspect the invention disclosed herein is directed to compounds ofFormula I and pharmaceutically acceptable salts thereof, which areuseful in the treatment of prostate, breast, ovarian, liver, kidney,colon, pancreatic, human chronic lymphocytic leukemia, melanoma andother cancers. In another aspect the invention is directed to a methodof preventing the onset of and/or recurrence of acute and chronicmyeloid leukemia, as well as other cancers. The invention also includespharmaceutical compositions comprising a therapeutically effectiveamount of compound of Formula I, or a pharmaceutically acceptable saltthereof. The invention disclosed herein is also directed to methods oftreating prostate, breast, ovarian, liver, kidney, colon, pancreatic,human chronic lymphocytic leukemia, melanoma and other cancers. Theinvention disclosed herein is further directed to methods of treatingprostate, breast, colon, pancreatic, human chronic lymphocytic leukemia,melanoma and other cancers comprising administration of atherapeutically effective amount of a selective PPARα antagonist. Themethods include administering to the subject an effective amount of acompound of Formula (I) (and/or a compound of any of the other formulaedescribed herein) or a salt (e.g., a pharmaceutically acceptable salt)thereof as defined anywhere herein. In another aspect, the use of acompound of Formula (I) (and/or a compound of any of the other formulaedescribed herein) or a salt (e.g., a pharmaceutically acceptable salt)thereof as defined anywhere herein in the preparation of, or for use as,a medicament for the treatment (e.g., controlling, alleviating, orslowing the progression of) or prevention (e.g., delaying the onset ofor reducing the risk of developing) of one or more diseases, disorders,or conditions caused by, or associated with, prostate, breast, ovarian,liver, kidney, colon, pancreatic, human chronic lymphocytic leukemia,melanoma and other cancers.

In one aspect the invention is directed a method of treating a cancerwhich is negatively impacted by diminution in its metabolism via fattyacid oxidation, comprising administration of a therapeutically effectiveamount of a compound of Formula I (and/or a compound of any of the otherformulae described herein) or a salt (e.g., a pharmaceuticallyacceptable salt). In another aspect, the invention is directed to amethod of treating a cancer having a metabolism that is reliant on fattyacid oxidation, comprising administration of a therapeutically effectiveamount of a compound of Formula I (and/or a compound of any of the otherformulae described herein), or a pharmaceutically acceptable saltthereof.

Administration

The compounds and compositions described herein can, for example, beadministered orally, parenterally (e.g., subcutaneously,intracutaneously, intravenously, intramuscularly, intraarticularly,intraarterially, intrasynovially, intrasternally, intrathecally,intralesionally and by intracranial injection or infusion techniques),by inhalation spray, topically, rectally, nasally, buccally, vaginally,via an implanted reservoir, by injection, subdermally,intraperitoneally, transmucosally, or in an ophthalmic preparation, witha dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, (e.g., fromabout 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, fromabout 1 to about 100 mg/kg, from about 1 to about 10 mg/kg) every 4 to120 hours, or according to the requirements of the particular drug. Theinterrelationship of dosages for animals and humans (based on milligramsper meter squared of body surface) is described by Freireich et al.,Cancer Chemother. Rep. 50, 219 (1966). Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537(1970). In certain embodiments, the compositions are administered byoral administration or by injection. The methods herein include theadministration of an effective amount of compound or compoundcomposition to achieve the desired or stated effect. Typically, thepharmaceutical compositions of this invention will be administered fromabout 1 to about 6 times per day or alternatively, as a continuousinfusion. Such administration can be used as a chronic or acute therapy.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Dosage forms include from about 0.05 milligrams to about 2,000milligrams (e.g., from about 0.1 milligrams to about 1,000 milligrams,from about 0.1 milligrams to about 500 milligrams, from about 0.1milligrams to about 250 milligrams, from about 0.1 milligrams to about100 milligrams, from about 0.1 milligrams to about 50 milligrams, orfrom about 0.1 milligrams to about 25 milligrams) of a compound ofFormula I (and/or a compound of any of the other formulae describedherein) or a salt (e.g., a pharmaceutically acceptable salt) thereof asdefined anywhere herein. The dosage forms can further include apharmaceutically acceptable carrier and/or an additional therapeuticagent.

In one aspect the compounds of the invention may be co-administered withone or more additional anti-cancer agents. The additional anti-canceragents include, but are not limited to alkylating agents such ascyclophosphamide, chlorambucil, mecloreethamine, ifosfamide, ormelphalan; antimetabolites such as methotrexate, cytarabine,fludarabine, 6-mercaptopurine, azathioprene, pyrimidines, or5-fluorouracil; antimitotic agents such as vincristine, paclitaxel,vinorelbine or docetaxaxel; a topoisomerase inhibitors such asdoxorubicin or irinotecan; platinum derivatives such as cisplatin,carboplatin or oxaliplatin; hormone therapeutics such as tamoxifen;aromatase inhibitors such as bicalutamide, anastrozole, exemestane orletrozole; signaling inhibitors such as imatinib, gefitinib orerlotinib; monoclonal antibodies such as rituximab, trastuzumab,gemtuzumab or ozogamicin; differentiating agents such as tretinoin orarsenic trioxide; antiangiogenic agents such as bevacizumab, sorafinibor sunitinib; biologic response modifiers such as interferon-alpha;topoisomerase inhibitors such as camptothecins (including irinotecan andtopotecan), amsacrine, etoposide, etoposide phosphate, or teniposide;cytotoxic antibiotics such as actinomycin, anthracyclines includingdoxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin,bleomycin, plicamycin or mitomycin; vinca alkaloids such as vincristine,vinblastine, viorelbine or vindesine; or podophyllotoxins such asetoposide and teniposide; or mTOR inhibitors such as rapamycin,temsirolimus and everolimus.

Other anti-cancer agents for use in combination with the compoundsinclude one or more of the following: abiraterone, adriamycin,dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; everolimus; fadrozole hydrochloride; fazarabine;fenretinide; floxuridine; fludarabine phosphate; fluorouracil;flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabinehydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide;iimofosine; interleukin II (including recombinant interleukin II, orrlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1;interferon alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; metformin, methotrexate; methotrexate sodium;metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; rapamycin; riboprine; rogletimide; safingol; safingolhydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin;spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin;streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur;teloxantrone hydrochloride; temoporfin; temsirolimus; teniposide;teroxirone; testolactone; thiamiprine; thioguanine; thiotepa;tiazofurin; tirapazamine; toremifene citrate; trestolone acetate;triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

In certain embodiments, the additional agents may be administeredseparately, as part of a multiple dose regimen, from the compounds ofthis invention (e.g., sequentially, or on different overlappingschedules with the administration of one or more compounds of Formula(I) (and/or a compound of any of the other formulae including anysubgenera or specific compounds thereof)). In other embodiments, theseagents may be part of a single dosage form, mixed together with thecompounds of this invention in a single composition. In still anotherembodiment, these agents can be given as a separate dose that isadministered at about the same time as one or more compounds of Formula(I) (and/or a compound of any of the other formulae including anysubgenera or specific compounds thereof) are administered (e.g.,simultaneously with the administration of one or more compounds ofFormula (I) (and/or a compound of any of the other formulae includingany subgenera or specific compounds thereof)). When the compositions ofthis invention include a combination of a compound of the formulaedescribed herein and one or more additional therapeutic or prophylacticagents, both the compound and the additional agent can be present atdosage levels of between about 1 to 100%, and more preferably betweenabout 5 to 95% of the dosage normally administered in a monotherapyregimen.

The compositions of this invention may contain any conventionalnon-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.In some cases, the pH of the formulation may be adjusted withpharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form.

The compositions of this invention may be orally administered in anyorally acceptable dosage form including, but not limited to, capsules,tablets, emulsions and aqueous suspensions, dispersions and solutions.In the case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried corn starch. Whenaqueous suspensions and/or emulsions are administered orally, the activeingredient may be suspended or dissolved in an oily phase that is thencombined with emulsifying and/or suspending agents. If desired, certainsweetening and/or flavoring and/or coloring agents may be added.

Biological Function

The utility of the invention can be demonstrated by one or more of thefollowing methods or other methods known in the art:

Human PPARα Reporter Assay

The screening of test compounds for agonist or antagonist activitiesagainst human PPARα receptors was performed using a commercial kit,Human PPARα Reporter Assay System (Indigo Biosciences, Cat. #IB00111).

This nuclear receptor assay system utilizes proprietary non-humanmammalian cells engineered to provide constitutive, high-levelexpression of Human PPARα. Because these cells incorporate aPPARα-responsive luciferase reporter gene, quantifying expressedluciferase activity provides a sensitive surrogate measure of PPARαactivity in the treated cells. The primary application of this reporterassay system is in the screening of test samples to quantify anyfunctional activity, either agonist or antagonist, that they may exertagainst human PPARα. While this assay may be used to measure agonism,each of the Examples, infra, exhibits antagonism rather than agonism.Briefly, the reporter cells are dispensed into wells of the assay plateand then immediately dosed with test compounds. Following an overnightincubation, the treatment media are discarded and Luciferase DetectionReagent (LDR) is added. The intensity of light emission from the ensuingluciferase reaction provides a sensitive measure that is directlyproportional to the relative level of PPARa activation in the reportercells.

Target Selectivity Assays

To determine species selectivity, a Mouse PPARα Reporter Assay Systemwas used (Indigo Biosciences, Cat. #M00111). Activity of test compoundsto antagonize or agonize other isoforms of human PPAR, for example β/δand γ, were assessed using the corresponding kits from IndigoBiosciences (Cat. #1B00121 and #IB00101, respectively). In addition toPPAR activity, compounds were also screened for activity against othernuclear hormone receptors including Estrogen Receptor β, GlucocorticoidReceptor and Thyroid Receptor β using commercially available kits(Indigo Biosciences, Cat. #1B00411, IB00201 and IB01101, respectively).Each assay system from Indigo Biosciences uses technology analogous tothe human PPARα kit, with the variance being that the cells used foreach assay were engineered to over-express the receptor of interest. Inaddition, the appropriate receptor agonist (included with each kit) wasused at ˜EC80 for assays in which antagonist potency was being assessed.

Target Selectivity—Counterscreen Assay Results

PPAR PPAR PPAR Thyroid Glucocorticoid Estrogen alpha beta/delta gammaReceptor β Receptor Receptor β Example IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM)IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 6 58 13265 39845 30849 18191 19444

Measuring Fatty Acid Oxidation Using ³H Palmitate

Fatty acid oxidation is measured using ³H palmitate metabolism into ³H₂Oas described previously (Nieman et al., 2011). Briefly, cells (e.g.HepG2, PC3 and CLL) are plated in growth media and allowed to adhereovernight. Cells are then treated with compound or 40 μM etomoxir (aninhibitor of fatty acid oxidation) as control. After treatment, cellsare washed with DPBS followed by incubation in assay buffer (growthmedia, ³H palmitate and compound). After incubation, media is collectedand proteins precipitated with 5% tricholoroacetic acid. The precipitateis pelleted by centrifugation and the supernatant collected. Anyremaining ³H palmitate in the supernatant is then removed bypurification over a Dowex anion exchange column. ³H₂O is then measuredby scintillation counting.

Measurement of Cell Viability

Purified CLL cells were cultured at 2×10⁵ cells/200 μL of RPMI1640supplemented with 10% FCS in 96-well plates under various treatmentconditions. Determination of CLL cell viability was based on theanalysis of mitochondrial transmembrane potential (ΔΨm) using3,3′-dihexyloxacarbocyanine iodide (DiOC6) (Invitrogen) and cellmembrane permeability to propidium iodide (PI) (Sigma). For viabilityassays, 100 μL of the cell culture was collected at the indicated timepoints and transferred to polypropylene tubes containing 100 μL of 40 μMDiOC6 and 10 μg/mL PI in culture media. The cells were then incubated at37° C. for 15 min and analyzed within 30 min by flow cytometry using anAccuri C6 flow cytometer. The percentage of viable cells was determinedby gating on PI negative and DiOC6 bright cells.

In Vivo PD Model: PPAR Alpha Agonist-Induced Changes in Liver GeneExpression

CD-1 mice were treated with test compound 1-2 hours prior to oral gavagewith the PPAR alpha agonist WY14,643 (3 mg/kg). For the 1 daypharmacodynamic model, animals were euthanized 6 hours after agonisttreatment. For the 3 day pharmacodynamic model, mice were dosed againwith antagonist and WY14,643 on day 2 and day 3. In this case, mice wereeuthanized 6 hours following WY14,643 on day 3. Upon termination, bloodwas collected for DMPK analysis. Liver was collected, placed into Trizoland stored at −80° C. until processing. RNA was extracted from thawedand homogenized tissue using standard Trizol RNA isolation methods.RT-PCR was performed on the extracted RNA using primers specific forPPAR alpha regulated genes. Quantitative PCR was performed on theresulting cDNA and expression was normalized to β-actin.

In Vivo Cancer Model: B16F10 Model of Pulmonary Metastasis

B16F10 cells were cultured in standard growth media, harvested whenapproximately 50% confluent and injected into C57BL/6 mice via the tailvein (50,000 cells per mouse in 200 μL). Mice were treated daily withtest compound. On day 21, mice were euthanized. Lungs were harvested andplaced into Fekete's solution overnight to facilitate visualization ofthe tumors. Black nodules were enumerated.

FIG. 1 shows inhibition of metastasis of B16F10 melanoma cells to thelung following oral doses of Example 6 at 0.3, 3 and 30 mg/kg.Statistics were performed by ANOVA with Dunnett's Multiple ComparisonTest post-hoc to determine statistical differences from vehicletreatment group. * denotes P<0.05, while *** denotes P<0.001.

Synthesis

The starting materials used for the synthesis are either synthesized orobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, VWR Scientific, andthe like. General methods for the preparation of compounds can bemodified by the use of appropriate reagents and conditions for theintroduction of the various moieties found in the structures areprovided herein.

In some embodiments, compounds described herein are prepared as outlinedin the following general synthetic scheme.

General Synthetic Scheme for Exemplary Compounds

For Heterocycle containing central rings:

Preparation of Intermediates 4-(3-Bromophenyl)butanoic acid

Step 1: To a solution of 3-bromobenzaldehyde (5.00 g, 27.0 mmol) in DMF(18 mL) was added sodium cyanide (331 mg, 6.8 mmol) and the resultingsolution was heated at 45° C. for 30 min. A solution of acrylonitrile(1.55 mL, 23.7 mmol) in DMF (2 mL) was added dropwise over a period of20 minutes and the heating continued for 3 hrs. The solution was allowedto cool after which AcOH (1 mL) was added, the reaction mixturepartitioned between EtOAc and water, the organic phase extracted, dried(MgSO₄), filtered and evaporated in vacuo. The residue was purifiedusing silica gel chromatography (0 to 30% EtOAc in hexanes) to afford3.1 g of 4-(3-bromophenyl)-4-oxobutanenitrile as a yellow oil.

Step 2: To a solution of the isolated nitrile (3.1 g, 13.0 mmol) inethylene glycol (22 mL) was added water (0.5 mL), hydrazine monohydrate(1.5 mL) and potassium hydroxide (3.34 g). The reaction mixture washeated to 195° C. until analysis by LCMS indicated complete reaction,after which it was allowed to cool to room temperature, diluted withwater and acidifed to pH ˜2 with 2N HCl. The resulting solution wasextracted with EtOAc, dried (MgSO₄), filtered and evaporated in vacuo.Purification of the residue on silica gel (0 to 30% acetone in hexanes)afforded 2.9 g of the title acid. 4-(3-Bromophenyl)butanehydrazide:

To a solution of 4-(3-bromophenyl)butanoic acid (2.9 g, 11.9 mmol) inTHF (50 mL) was added carbonyldiimidazole (2.32 g, 14.3 mmol) andstirred for 1.5 hrs. Hydrazine monohydrate (2.4 mL, ˜4 eq.) was addedand the reaction was complete after 30 minutes as judged by LCMSanalysis. The solution was partitioned between EtOAc and water, theorganic phase extracted, dried (MgSO₄), filtered and evaporated toafford the title compound which was then used without furtherpurification.

3-(3-(3-Bromophenyl)propyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one

Step 1: The previously isolated 4-(3-bromophenyl)butanehydrazide (11.9mmol) was dissolved in THF (50 mL) to which was added ethyl isocyanate(1.13 mL, 14.3 mmol). After stirring at room temperature for 12 hrs, thesolution was evaporated to dryness to afford2-(4-(3-bromophenyl)butanoyl)-N-ethylhydrazinecarboxamide which was thenused without further purification.

Step 2: To a solution of the isolated carboxamide in MeOH (50 mL) wasadded KOH (6 g) and the reaction mixture was heated to reflux for 16hrs. After complete reaction as judged by LCMS analysis, the solvent wasremoved and the residue diluted in DCM and acidified with 1N HCl withcooling. Extraction of the resulting mixture with DCM, drying of theorganic phase (MgSO₄), filtration and evaporation of the filtrate invacuo afforded crude3-(3-(3-bromophenyl)propyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one whichcould be purified on silica gel (0 to 100% EtOAc in hexanes).

3-(3-(3-Bromophenyl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one

To a solution of3-(3-(3-bromophenyl)propyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (27.7 g,89.3 mmol) in DMF (200 mL) was added potassium carbonate (40.0 g, 288.7mmol) followed by 4-tert-butylbenzylbromide (17.2 mL, 93.8 mmol) and theresulting suspension was stirred vigorously for 48 hrs at roomtemperature. The reaction mixture was diluted with EtOAc, washed withwater (×2), dried (MgSO₄), filtered and evaporated in vacuo.Purification of the residue on silica gel (0 to 50% EtOAc in hexanes)afforded the title compound as a colorless oil.

1-(4-(tert-Butyl)benzyl)-4-ethyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of3-(3-(3-bromophenyl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(11.7 g, 25.5 mmol) in dioxane (150 mL) was added potassium acetate (7.5g, 76.5 mmol), bis(pinacolato)diboron (7.8 g, 30.7 mmol) and Pd(dppf)Cl₂(750 mg). The resulting solution was sparged with dry nitrogen for 15minutes and then heated to 85° C. for a period of 3 hrs. The solvent wasremoved in vacuo and the residue partitioned between EtOAc and water.The organic phase was separated, dried (MgSO₄), filtered and evaporatedto give the crude boronate. This was further purified on silica gel,eluting with 0 to 50% EtOAc in hexanes, to afford the title boronate asa colorless oil.

Methyl 2-(5-bromo-2-hydroxyphenyl)acetate

To a solution of 2-(2-hydroxyphenyl)acetic acid (15.6 g, 103 mmol) inMeOH (350 mL) was added tetrabutylammonium tribromide (50 g, 103 mmol)in small portions over a 10 minute period. After stirring at ambienttemperature for 24 hrs, the solvent was evaporated and the residue takenup in EtOAc, washed with 1N HCl, extracted with EtOAc, the organicphases dried (MgSO₄), filtered and evaporated. The residue was purifiedon silica gel eluting with a gradient of 30% EtOAc in hexanes to affordthe title compound as a colorless solid.

Methyl 2-(5-bromo-2-ethoxyphenyl)acetate

To a solution of methyl 2-(5-bromo-2-hydroxyphenyl)acetate (1.0 g, 4.1mmol) in DMF (8 mL) was added cesium carbonate (2.66 g, 8.2 mmol) andiodoethane (392 μL, 4.9 mmol) and stirred at rt for 2 hrs. Aftercompletion, the reaction mixture was partitioned between EtOAc andwater, the organic phase separated, washed with water, dried (MgSO₄),filtered and evaporated in vacuo. The residue was purified on silica geleluting with a gradient of 0 to 10% EtOAc in hexanes to afford the titlecompound as a colorless oil.

Methyl 2-(5-bromo-2-methoxyphenyl)acetate

Prepared in an analogous fashion to the aforementioned ethyl derivativeusing methyl iodide as electrophile.

Methyl 2-(5-bromo-2-propoxyphenyl)acetate

Prepared in an analogous fashion to the aforementioned ethyl derivativeusing 1-bromopropane as electrophile.

Methyl 2-(2-(benzyloxy)-5-bromophenyl)acetate

Prepared in an analogous fashion to the aforementioned ethyl derivativeusing benzylbromide as electrophile.

Methyl 2-(5-bromo-2-(cyclopropylmethoxy)phenyl)acetate

Prepared in an analogous fashion to the aforementioned ethyl derivativeusing (bromomethyl)cyclopropane as electrophile.

Methyl 2-(5-bromo-2-(2-(dimethylamino)ethoxy)phenyl)acetate

Prepared in an analogous fashion to the aforementioned ethyl derivativeusing 2-chloro-N,N-dimethylamine hydrochloride as electrophile in thepresence of catalytic amount of tetrabutylammonium iodide. Purified onsilica using a 0 to 60% gradient of acetone in hexanes.

Methyl 5-bromo-2-propoxybenzoate

Prepared in an analogous fashion to methyl2-(5-bromo-2-ethoxyphenyl)acetate but starting with5-bromo-methylsalicylate as starting material.

2-(4-Bromo-2-methoxyphenyl)acetonitrile

Step 1: To a solution of 5-bromo-2-methylphenol (1.5 g, 8.0 mmol) in DMF(10 mL) was added Cs₂CO₃ (3.9 g, 12.0 mmol) followed by iodomethane(0.55 mL, 8.8 mmol). The resulting suspension was stirred vigorously for24 hrs after which it was diluted with EtOAc and washed with water. Theorganic phase was dried (MgSO₄), filtered, evaporated in vacuo and theresidue purified on silica gel (0 to 5% EtOAc gradient in hexanes) toafford 4-bromo-2-methoxy-1-methylbenzene as a colorless oil.

Step 2: To a solution of 4-bromo-2-methoxy-1-methylbenzene (1.2 g, 6.0mmol) in C₁₋₄ (15 mL) was added N-bromosuccinimide (1.17 g, 6.5 mmol)and benzoyl peroxide (50 mg). The resulting mixture was heated underreflux for 6 hrs, allowed to cool, evaporated and the residue purifiedon silica gel eluting with a gradient of 0 to 10% EtOAc in hexanes. Theisolated bromide (440 mg, 1.6 mmol) was then dissolved in DMF (2 mL) andpotassium cyanide (204 mg, 3.1 mmol) added. After stirring for 48 hrs atroom temperature, the solution was diluted with EtOAc, washed withwater, the organic phase separated, dried (MgSO₄), filtered andevaporated in vacuo. Purification of the residue on silica gel (0 to 10%EtOAc in hexanes) afforded the title compound.

2-(4-Bromo-2-ethoxyphenyl)acetonitrile

Prepared in an analogous fashion to the methoxy derivative usingiodoethane in Step 1.

2-(4-Bromo-2-propoxyphenyl)acetonitrile

Prepared in an analogous fashion to the methoxy derivative using1-bromopropane in Step 1.

2-(5-Bromo-2-isopropoxyphenyl) acetonitrile

Prepared in an analogous fashion to2-(4-bromo-2-ethoxyphenyl)acetonitrile utilizing 4-bromo-2-methylphenolas starting material and alkylating the phenol under the followingconditions: To a solution of 4-bromo-2-methylphenol (3.5 g, 18.7 mmol)in DMSO (10 mL) was added K₂CO₃ (5.2 g, 37.5 mmol) and 2-iodopropane(2.25 mL, 22.5 mmol) and the resulting suspension was heated to 60° C.in a sealed vial for 16 hrs. After complete reaction the solution wasdiluted in EtOAc, washed with water, the organic phase separated, dried(MgSO₄), filtered and evaporated in vacuo. The isolated residue waspurified on silica gel (0 to 5% EtOAc in hexanes) to afford4-bromo-1-isopropoxy-2-methylbenzene as a colorless oil.

1-(4-(tert-Butyl)benzyl)-N-ethylhydrazinecarboxamide,monomethanesulfonate (Intermediate M)

Step 1: In a 500 mL Parr shaker flask was dissolved (E)-tert-butyl2-(4-(tert-butyl)benzylidene)hydrazinecarboxylate (15.0 g, 54.0 mmol,prepared according to the procedure described in Braden, T. M. et al.,Org. Process Res. Dev. 2007, 11, 431-440) in iPrOH (75 mL) and EtOAc (25mL). To this was then added Adam's catalyst (0.7 g, 0.3 mmol) and theresulting suspension was thoroughly deoxygenated via subsurface purgingwith nitrogen. The reaction vessel was then connected to a Parr shakerand the reaction suspension was shaken under 50 psi of H₂ for 3 days (oruntil no further consumption of hydrogen gas could be discerned). Atthis point, the excess H₂ was discharged from the vessel and thereaction was immediately quenched with DCM. The deactivated catalyst wasthen removed via filtration through a pad of DCM-wetted celite and theinsolubles were washed thoroughly with DCM. The filtrate thus obtainedwas concentrated in vacuo to furnish a colorless oil. This residue wasthen transferred as an iPrOH (100 mL) solution to a 500 mL Parr shakerflask and added another batch of Adam's catalyst (0.7 g, 0.3 mmol).After de-oxygenation via subsurface purging with nitrogen, the resultingsuspension was shaken under 50 psi of H₂ for 2 more days. Finally,excess H₂ was discharged from the vessel and the reaction was quenchedwith DCM. The insolubles were then removed via filtration through a padof DCM-wetted celite and the celite bed was washed thoroughly with DCM.Concentration of the filtrate thus obtained in vacuo furnished 15.1 g oftert-butyl 2-(4-(tert-butyl)benzyl)hydrazinecarboxylate (quantitativeyield).

Step 2: In an oven-dried 1 L RBF equipped with a magnetic stirrer wasdissolved tert-butyl 2-(4-(tert-butyl)benzyl)hydrazinecarboxylate (15.1g, 54.0 mmol) in anhydrous DCM (500 mL). To this was then added neatethyl isocyanate (6.7 mL, 86 mmol) drop-wise over a period of 15 min andthe resulting solution was allowed to stir under nitrogen at RT over 48h. The volatiles were then removed in vacuo and the resulting residuewas co-evaporated with heptanes (3×500 mL) to furnish 19.5 g oftert-butyl2-(4-(tert-butyl)benzyl)-2-(ethylcarbamoyl)hydrazinecarboxylate(quantitative yield).

Step 3: In an oven-dried 1 L RBF equipped with a magnetic stirrer wasdissolved tert-butyl2-(4-(tert-butyl)benzyl)-2-(ethylcarbamoyl)hydrazinecarboxylate (19.5 g,54.0 mmol) in anhydrous DCM (500 mL). To this was then added neat MsOH(4.7 mL, 73 mmol) drop-wise over a period of 15 min and the resultingsolution was allowed to stir under nitrogen at RT over 16 h. Thevolatiles were then in vacuo and the resulting residue was co-evaporatedwith DCM (3×500 mL) and MeOH (3×500 mL) to furnish 19.1 g (99% yield) ofintermediate (M) as a pale yellow foam.

Example 1:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)aceticacid

Step 1: To a solution of3-(3-(3-bromophenyl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(250 mg, 0.55 mmol) in a mixture of DME (5 mL) and water (2 mL) wasadded potassium carbonate (191 mg, 1.38 mmol) and3-ethoxycarbonylmethylphenylboronic acid (191 mg, 0.66 mmol). Aftersparging the mixture with nitrogen, Pd(PPh₃)₄(30 mg, cat.) was added andthe reaction heated at 85° C. for 3 hrs. The reaction as allowed tocool, partitioned between EtOAc and water, the organic phase extracted,dried (MgSO₄), filtered and evaporated in vacuo. The residue waspurified on silica gel eluting with a gradient of 0 to 60% EtOAc inhexanes to afford the ester of the title compound.

Step 2: To a solution of the aforementioned ester (200 mg, 0.37 mmol) ina mixture of THF (4 mL), MeOH (2 mL) and water (2 mL) was added lithiumhydroxide monohydrate (100 mg, 2.4 mmol) and the reaction stirred atroom temperature until complete ester hydrolysis was evident asdetermined by LCMS analysis. Solid citric acid was added to adjust pH to˜4 and the solution partitioned between EtOAc and water. The organicphase was extracted, dried (MgSO₄), filtered and evaporated to affordthe title acid as a colorless solid.

The following examples (2-4,6-11, 13, 15-19, 28-30, 32 and 33) wereprepared in an analogous fashion to Example 1 using the requisitecommercially available boronic acid (or pinacol ester) coupling partnerand subsequent hydrolysis.

Example 2:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-yl)aceticacid

Example 3:3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-carboxylicacid

Example 4:3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-carboxylicacid

Example 5:1-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)cyclopropanecarboxylicacid

Preparation of 1-(5-bromo-2-ethoxyphenyl)cyclopropanecarbonitrile

Step 1: To a solution of 4-bromo-2-methylphenol (5.0 g, 26.7 mmol) inDMF (20 mL) was added Cs₂CO₃ (13.0 g, 39.9 mmol) and iodoethane (2.6 mL,32.5 mmol). The reaction was stirred vigorously for 24 hrs after whichthe suspension was partitioned between EtOAc and water, the organicphase extracted, wash with water, dried (MgSO₄), filtered and evaporatedto afford 4-bromo-1-ethoxy-2-methylbenzene used without furtherpurification.

Step 2: To a solution of 4-bromo-1-ethoxy-2-methylbenzene (5.0 g, 23.1mmol) in C₁₋₄ (80 mL) was added N-bromosuccinimide (4.93 g, 27.6 mmol)and benzoyl peroxide (100 mg, cat.). The reaction mixture was thenheated to reflux for a period of 3 hrs after which it was allowed tocool, partially evaporated then filtered to remove the succinimide. Thefiltrate was then evaporated to dryness to afford the benzylbromidewhich was used without further purification.

Step 3: To the crude 4-bromo-2-(bromomethyl)-1-ethoxybenzene (23.1 mmol)isolated previously was added DMF (20 mL) and potassium cyanide (2.26 g,34.7 mmol) and the slurry stirred at room temperature for 48 hrs. Thereaction mixture was partitioned between EtOAc and water, the organicphase separated, dried (MgSO₄), filtered and evaporated to afford amixture of the mono and bis cyanomethyl derivatives. Purification of themixture using silica gel chromatography (0 to 10% EtOAc in hexanes)afforded 2.5 g of 2-(5-bromo-2-ethoxyphenyl)acetonitrile.

Step 4: To 2-(5-bromo-2-ethoxyphenyl)acetonitrile (1.0 g, 4.16 mmol) in2 mL of aqueous KOH (50%) was added tetrabutylammonium bromide (200 mg)and 1,2-dibromoethane (541 μL, 6.2 mmol) and heated in a sealed vial at50° C. with vigorous stirring for 4 hrs. The mixture was partitionedbetween EtOAc and 1N HCl, the organic phase separated, dried (MgSO₄),filtered and evaporated in vacuo. The afforded1-(5-bromo-2-ethoxyphenyl)cyclopropanecarbonitrile was used withoutfurther purification.

Example 5 was prepared analogously to example 1 using1-(5-bromo-2-ethoxyphenyl)cyclopropanecarbonitrile as the couplingpartner. Furthermore, hydrolysis of the resulting nitrile aftercross-coupling was performed using KOH in ethylene glycol and water at150° C.

Example 6:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)aceticacid

Example 7:1-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)cyclopropanecarboxylicacid

Example 8:1-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-yl)cyclopropanecarboxylicacid

Example 9:3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methoxy-[1,1′-biphenyl]-3-carboxylicacid

Example 10:3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-carboxylicacid

Example 11:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-propoxy-[1,1′-biphenyl]-3-yl)aceticacid

Example 12:N-(6-(3-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)phenyl)pyridin-3-yl)benzenesulfonamide

Step 1: To a solution of3-(3-(3-bromophenyl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(300 mg, 0.6 mmol) in a mixture of DME (5.5 mL) and water (2.5 mL) wasadded potassium carbonate (250 mg, 1.80 mmol) and3-amino-6-bromopyridine (135 mg, 0.78 mmol). After sparging the mixturewith nitrogen, Pd(PPh₃)₄(30 mg, cat.) was added and the reaction heatedat 85° C. for 6 hrs. The reaction was allowed to cool, partitionedbetween EtOAc and water, the organic phase extracted, dried (MgSO₄),filtered and evaporated in vacuo. The residue was purified on silica geleluting with a gradient of 0 to 60% EtOAc in hexanes to afford3-(3-(3-(5-aminopyridin-2-yl)phenyl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.

Step 2: To a solution of the isolated3-(3-(3-(5-aminopyridin-2-yl)phenyl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(50 mg, 0.106 mmol) in pyridine (0.8 mL) was added benzenesulfonylchloride (14 μL, 0.106 mmol). After stirring for 48 hrs, the reactionmixture was diluted with EtOAc, washed with water, dried (MgSO₄),filtered and evaporated in vacuo. The isolated residue was purified onsilica gel eluting with a gradient of 0 to 5% MeOH in CHCl₃ to affordthe title compound.

Example 13:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methoxy-[1,1′-biphenyl]-3-yl)aceticacid

Example 14:1-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methyl-[1,1′-biphenyl]-3-yl)cyclopropanecarboxylicacid

Preparation of 1-(5-bromo-2-methylphenyl)cyclopropanecarbonitrile

Step 1: To a suspension of LiAlH₄ (0.75 g, 3.11 mmol) in diethyl ether(8 mL) at 0° C. was added a solution of methyl 5-bromo-2-methylbenzoate(949 mg, 4.14 mmol) in diethyl ether (2 mL) dropwise. The reactionmixture was allowed to slowly warm to rt, then quenched with EtOAc,partitioned between EtOAc and 2N HCl and extracted (EtOAc). The organicphase was washed with water, dried (MgSO₄), filtered and evaporated invacuo to afford the crude alcohol which can be used without furtherpurification.

Step 2: To the aforementioned alcohol (818 mg, 4.1 mmol) in diethylether (10 mL) cooled to 0° C. was added PBr₃ (0.2 mL, 2.07 mmol) andstirred at 0° C. for 1 hr. The reaction was then quenched with water,diluted with ether, washed with sodium bicarbonate solution, the organicphase separated and dried (MgSO₄), filtered and evaporated yielding 726mg of the benzyl bromide.

Step 3: To 4-bromo-2-(bromomethyl)-1-methylbenzene (726 mg, 2.75 mmol)in DMF (8 mL) was added sodium cyanide (142 mg, 2.89 mmol) and theresulting suspension heated to 50° C. for 4 hrs. The reaction mixturewas diluted with EtOAc, washed with water then brine, dried (MgSO₄),filtered and evaporated in vacuo. The isolated residue was purified onsilica gel eluting with a gradient of 0 to 50% EtOAc in hexanes toafford 2-(5-bromo-2-methylphenyl)acetonitrile.

Step 4: 1-(5-bromo-2-methylphenyl)cyclopropanecarbonitrile was thenprepared analogously to the method described in Example 5, Step 4.

Example 14 was completed under the same conditions as described forExample 5.

Example 15:2-(4-(Benzyloxy)-3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)aceticacid

Example 16:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-(cyclopropylmethoxy)-[1,1′-biphenyl]-3-yl)aceticacid

Example 17:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-fluoro-[1′-biphenyl]-3-v1)acetic acid

Example 18:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-6-ethoxy-[1,1′-biphenyl]-3-yl)aceticacid

Example 19:3′(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-propoxy-[1,1′-biphenyl]-3-carboxylicacid

Example 20:N-((3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)methyl)benzenesulfonamide

Step 1: A mixture of1-(4-(tert-butyl)benzyl)-4-ethyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1H-1,2,4-triazol-5(4H)-one(223 mg, 0.443 mmol), 3-bromobenzyl amine (98 mg, 0.532 mmol, 1.2 eq)and potassium carbonate (183 mg, 1.33 mmol, 3 eq) were taken up in DME(2 mL) and water (1 mL) solution. To thistetrakis(triphenylphosphine)palladium(0) (52 mg, 0.0443 mmol, 0.1 eq)was added and the resulting mixture was stirred at 85° C. under anatmosphere of N₂ for 24 hr. The reaction mixture was cooled to roomtemperature and the solvent was removed under vacuum. The crude materialwas partitioned between water and EtOAc. The aqueous layer was extractedwith EtOAc (3×20 mL) and the organic layer was dried over anhydrousNa₂SO₄. The solvent was evaporated in vacuum to obtain the crudeproduct. The crude product was purified on flash column chromatography(silica gel, 0-70% EtOAc, 10% Methanol, 2.5% trieythylamine/Hexanes) toafford a white solid (84 mg, 40% yield) LC-MS: 483 (M+H)⁺.

Step 2: A mixture of3-(3-(3′-(aminomethyl)-[1,1′-biphenyl]-3-yl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(35 mg, 0.0726 mmol) and benzene sulfonylchloride (10 μL, 0.0798 mmol,1.1 eq) was stirred in pyridine (1 mL) at room temperature for 24 hr.The mixture was poured onto dichloromethane (40 mL) and washed withsaturated CuSO₄, water, and brine. The combined organic layers weredried over anhydrous Na₂SO₄, filtered and evaporated under vacuum toobtain the crude product. The crude product was purified on reversephase HPLC to afford a white foam (10 mg, 33%). LC-MS: 623 (M+H)+.

Example 21:3-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methoxy-[1,1′-biphenyl]-3-yl)propanoicacid

A mixture of1-(4-(tert-butyl)benzyl)-4-ethyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1H-1,2,4-triazol-5(4H)-one(70 mg, 0.139 mmol), 3-(5-bromo-2-methoxyphenyl) propanoic acid (43 mg,0.167 mmol, 1.2 eq) and potassium phosphate tribasic (118 mg, 0.556mmol, 4 eq) were taken up in DME (2 mL) and water (1 mL) solution. Tothis tris(dibenzylideneacetone)dipalladium(0) (4 mg, 0.0034 mmol, 0.025eq) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (5 mg, 0.011mmol, 0.08 eq) were added and the resulting mixture was stirred at 85°C. under an atmosphere of N₂ for 24 hr. The reaction mixture was cooledto room temperature and the solvent was removed under vacuum. The crudematerial was partitioned between water and EtOAc. The aqueous layer wasextracted with EtOAc (3×20 mL) and the organic layer was dried overanhydrous Na₂SO₄. The solvent was evaporated in vacuum to obtain thecrude product. The crude product was purified on reverse phase HPLC toafford a white solid (10 mg, 13% yield) LC-MS: 556 (M+H)+.

Example 22:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,1-difluoropropyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)aceticacid

Step 1: To a solution of 4-(3-bromophenyl)-4-oxobutanenitrile (1.11 g,4.66 mmol) in toluene (10 mL) was added Deoxyfluor (8.63 mL, 23.31 mmol,2.7 M solution in Toluene) followed by EtOH (0.16 mL, 2.80 mmol). Themixture was stirred at 80° C. for 16 hrs. The solution was cooled to rtand diluted with diethyl ether and a solution of saturated aqueousNaHCO₃. The organic layer was separated and washed sequentially withsaturated aqueous NaHCO₃, 1M aqueous HCl, and water. The organics wereconcentrated and residue was purified by column chromatography using0%-65% gradient EtOAc/Hexanes as eluent to afford 0.570 g (47% yield) of4-(3-bromophenyl)-4,4-difluorobutanenitrile.

Step 2:4-(3-Bromophenyl)-4,4-difluorobutanenitrile (0.57 g, 2.19 mmol),ethylene glycol (20 mL), water (2 mL), and KOH (0.701 g, 17.53 mmol)were combined and heated at 80° C. for 16 hrs. The solution was cooledto rt, diluted with EtOAc and quenched with 1M aqueous HCl. The organicswere separated and washed sequentially with 0.1M aqueous HCl and brine,filtered through a Na₂SO₄/paper plug and concentrated. The organics wereconcentrated and residue was purified by column chromatography using0%-50% gradient acetone/hexanes as eluent to afford 0.386 g (63% yield)of 4-(3-bromophenyl)-4,4-difluorobutanoic acid.

Step 3: 4-(3-Bromophenyl)-4,4-difluorobutanoic acid (0.20 g, 0.717mmol), Hunig's base (0.33 mL, 1.86 mmol) and2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (0.327 g, 0.86 mmol) were combined in anhydrous DMF(7 mL). The reaction solution was stirred for 40 min at rt, thenintermediate (M) (0.248 g, 0.717 mmol) was added. The resulting solutionwas allowed to stir at rt for 16 h. The reaction mixture was thendiluted with EtOAc and 1 N aq. HCl. The organics were separated andwashed sequentially with saturated aqueous NaHCO₃, water, and brine. Theorganic extract was then dried over sodium sulfate and filtered.Concentration of the filtrate afforded crude2-(4-(3-bromophenyl)-4,4-difluorobutanoyl)-1-(4-(tert-butyl)benzyl)-N-ethylhydrazinecarboxamide,which was used as is in the next step.

Step 4: To an EtOAc solution (8 mL) of2-(4-(3-bromophenyl)-4,4-difluorobutanoyl)-1-(4-(tert-butyl)benzyl)-N-ethylhydrazinecarboxamide(0.365 g, 0.717 mmol) was added camphorsulfonic acid (0.18 g, 0.717mmol) and the resulting solution was heated at reflux for 16 h. Thereaction mixture was then diluted with EtOAc and 1 N aq. HCl. Theorganics were washed sequentially with 1M NaOH and water, and thenconcentrated. The residue was purified by column chromatography using10%-90% gradient EtOAc/hexanes as eluent to afford 0.140 g (40% yield,two steps) of3-(3-(3-bromophenyl)-3,3-difluoropropyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.

Step 5: Under a nitrogen atmosphere,3-(3-(3-bromophenyl)-3,3-difluoropropyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(0.040 g, 0.081 mmol) and methyl2-(2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(0.029 g, 0.089 mmol) were dissolved in dioxane (3 mL) to which was thenadded a solution of saturated aqueous NaHCO₃ (1 mL). The resultingsolution was then subsurface purged with N₂ for 5 minutes after which,Pd(PPh)₄ (0.016 g, 0.014 mmol) was added. The resulting mixture wasstirred in a sealed pressure vessel at 90° C. for 16 hrs. The solutionwas cooled to rt and diluted with EtOAc and water. The organics werewashed once more with water and the solution was filtered through aNa₂SO₄/paper plug and concentrated. The residue was purified bypreparatory TLC using 20% acetone/hexanes as eluent to afford 0.029 g ofmethyl2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,1-difluoropropyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetate(59% yield).

Step 6: To a solution of methyl2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,1-difluoropropyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)acetate(0.029 g, 0.048 mmol) in THF (1 mL) and MeOH (1 mL) was added water(0.62 mL) and 1M aq. LiOH (0.38 mL, 0.37 mmol). The resulting mixturewas then stirred at 35° C. for 48 hrs. The solvents were evaporated andthe residue treated with EtOAc and a 20% aq. solution of citric acid.The organic layer was separated and extracted with water (2×). Theorganics were concentrated to afford 0.029 g (100% yield) of the titlecompound as a brown solid. LCMS (ESI), M+H 592.

Example 23:N-(6-(3-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,1-difluoropropyl)phenyl)pyridin-3-yl)benzenesulfonamide

Step 1:3-(3-(3-Bromophenyl)-3,3-difluoropropyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(0.110 g, 0.223 mmol), bis(pinacolato)diborane (0.074 g, 0.290 mmol),KOAc (0.066 g, 0.669 mmol) were dissolved in dioxane (4 mL) and theresulting solution was subsurface purged with N₂ for 5 minutes afterwhich, Pd(dppf)Cl₂ (0.016 g, 0.014 mmol) was added. The resultingmixture was stirred in a sealed pressure vessel at 85° C. for 16 hrs.The solution was cooled to rt and diluted with DCM and water. Theorganics were washed once more with water and the solution was filteredthrough a Na₂SO₄/paper plug and concentrated. The residue was purifiedby preparatory TLC using 40% EtOAc/hexanes as eluent to afford 0.065 gof1-(4-(tert-butyl)benzyl)-3-(3,3-difluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(54% yield).

Step 2: Under a nitrogen atmosphere,1-(4-(tert-butyl)benzyl)-3-(3,3-difluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(0.065 g, 0.120 mmol) from the previous step andN-(6-bromopyridin-3-yl)benzenesulfonamide (0.042 g, 0.133 mmol) weredissolved in dioxane (3 mL). To this solution was then added a solutionof saturated aqueous NaHCO₃ (1 mL) and the resulting biphasic mixturewas then subsurface purged with N₂ for 5 minutes. Finally, Pd(PPh)₄(0.014 g, 0.012 mmol) was added and the resulting mixture was stirred ina sealed pressure vessel at 85° C. for 16 hrs. The solution was cooledto rt, evaporated, and diluted with EtOAc and 1:1 brine/water. Theorganics were washed once more with water and brine. The organics werethen filtered through a Na₂SO₄/paper plug and concentrated. The residuewas purified by preparatory LCMS (C₁₈ reverse phase) using 0% to 100%CH₃CN/water as eluent to afford 0.013 g of the title compound (17%yield). LCMS (ESI), M+H 646.

Example 24:2-(5-(6-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyridin-2-yl)-2-methoxyphenyl)aceticacid

Step 1: To a degassed (sparged) solution of 2-bromo-6-chloropyridine(2.0 g, 10.4 mmol) in THF (75 mL) was added Pd(PPh₃)₄(200 mg) followedby a solution of (4-ethoxy-4-oxobutyl)zinc(II) bromide (0.5M in THF;20.8 mL, 20.8 mmol). After stirring at room temperature for 2 hrs, thesolution was poured on to a mixture of ice and 1N HCl, extracted withEtOAc, the organic phase separated, dried (MgSO₄), filtered andevaporated. The isolated residue was purified on silica gel (0 to 30%EtOAc in hexanes) to afford 1.4 g of ethyl4-(6-chloropyridin-2-yl)butanoate.

Step 2: Lithium hydroxide monohydrate (400 mg) was added to a solutionof ethyl 4-(6-chloropyridin-2-yl)butanoate (1.4 g, 7.0 mmol) in amixture of THF (20 mL), MeOH (8 mL) and water (8 mL). After stirring atroom temperature for 1 hr, the solution was diluted with EtOAc andwater. Solid citric acid was then added until an acidic pH was attainedand the organic phase separated, washed with water, dried (MgSO₄),filtered and evaporated to afford 4-(6-chloropyridin-2-yl)butanoic acid.The crude product thus obtained was used without further purification.

Step 3: To a solution of 4-(6-chloropyridin-2-yl)butanoic acid (600 mg,3.0 mmol) in DMF (15 mL) was added HATU (1.3 g, 3.42 mmol) followed byDIPEA (1.6 mL) and stirred at RT for 30 minutes. Intermediate (M) (1.2g, 3.47 mmol) was then added and the solution allowed to stir at rt for24 hrs. The reaction mixture was partitioned between EtOAc and water,the organic phase separated, dried (MgSO₄) and filtered. To the filtratewas then added camphorsulfonic acid (697 mg, 3.0 mmol) and the resultingmixture was heated to reflux for 24 hrs. After cooling, the solution wasneutralized following the addition of saturated aqueous NaHCO₃. Theorganic phase was then separated, dried (MgSO₄), filtered and evaporatedin vacuo. The residue thus obtained was purified on silica gel, elutingwith a gradient of 0 to 80% EtOAc in hexanes to afford1-(4-(tert-butyl)benzyl)-3-(3-(6-chloropyridin-2-yl)propyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one.

Step 4: The title compound was then obtained as previously described forExample 1, whereby the requisite boronate was cross-coupled and theresulting ester was then hydrolyzed under the same conditions.

Example 25:3-(3-(3′-(1H-Tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one

A mixture of3-(3-(3′-bromo-[1,1′-biphenyl]-3-yl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one(112 mg, 0.245 mmol), 3-(tetrazol-5 yl)phenylboronic acid (46 mg, 0.245mmol, 1.0 eq) and potassium phosphate tribasic (208 mg, 0.980 mmol, 4eq) were taken up in a DME (2 mL) and water (1 mL) solution. To this wasadded tris(dibenzylideneacetone)dipalladium(0) (6 mg, 0.0061 mmol, 0.025eq) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (20 mg, 0.049mmol, 0.2 eq), and the resulting mixture was stirred at 85° C. under anatmosphere of N₂ for 24 hr. The reaction mixture was cooled to roomtemperature and the solvent was removed under vacuum. The crude materialwas then partitioned between water and EtOAc. The aqueous layer wasseparated and extracted further with EtOAc (3×20 mL). The combinedorganic extracts were dried over anhydrous Na₂SO₄. The solvent wasevaporated in vacuum to obtain the crude product. The crude product waspurified on reverse phase HPLC to afford a white solid (20 mg, 16%yield) LC-MS: 521 (M+H)+.

Example 26:2-(5-(4-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyrimidin-2-yl)-2-ethoxyphenyl)aceticacid

Step 1: To a THF solution of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol)was added at 0° C. (4-ethoxy-4-oxobutyl)zinc(II) bromide (13.42 mL, 6.71mmol, 0.5 M in THF) followed by Pd(PPh)₄ (0.194 g, 0.167 mmol). Thereaction mixture thus obtained was then allowed to slowly warm to rt. ByTLC, it was noted that this reaction had stalled after 1.5 hr, soanother spatula tip of Pd(PPh)₄ was then added and reaction was allowedto continue at rt for another 16 hrs. The reaction mixture was thenpoured into ice-cold 0.5M aq. HCl solution and diluted with EtOAc andbrine. The organics were separated, washed once more with water and thenconcentrated. The residue was purified by column chromatography using0%-50% gradient EtOAc/hexanes as eluent to afford 0.930 g (60% yield) ofethyl 4-(2-chloropyrimidin-4-yl)butanoate.

Step 2: Under a nitrogen atmosphere, ethyl4-(2-chloropyrimidin-4-yl)butanoate (0.193 g, 0.842 mmol) and ethyl2-(2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile(0.220 g, 0.766 mmol) were dissolved in dioxane (8 mL) to which wasadded a solution of saturated aqueous NaHCO₃ (4 mL). The resultingsolution was then subsurface purged with N₂ for 5 minutes after which,Pd(PPh)₄ (0.088 g, 0.077 mmol) was added. The resulting mixture wasstirred in a sealed pressure vessel at 85° C. for 16 hrs. The solutionwas cooled to rt, evaporated, and diluted with EtOAc and brine. Theaqueous layer was extracted twice more with DCM and the combinedorganics were concentrated. The residue was purified by columnchromatography using 0%-60% gradient EtOAc/hexanes as eluent to afford0.144 g (54% yield) of4-(2-(3-(cyanomethyl)-4-ethoxyphenyl)pyrimidin-4-yl)butanoate.

Step 3: To a solution of ethyl4-(2-(3-(cyanomethyl)-4-ethoxyphenyl)pyrimidin-4-yl)butanoate (0.360 g,1.02 mmol) in THF (8 mL) and MeOH (8 mL) was added 1M aq. LiOH (8.02 mL,8.02 mmol). The resulting mixture was then stirred at rt for 1.5 hrs.The solvents were evaporated and the residue treated with EtOAc and a20% aq. solution of citric acid. The organic layer was separated andwashed with water (2×). The organics were then filtered through aNa₂SO₄/paper plug and concentrated. The resulting crude4-(2-(3-(cyanomethyl)-4-ethoxyphenyl)pyrimidin-4-yl)butanoic acid thusobtained was used directly in the next step.

Step 4: 4-(2-(3-(Cyanomethyl)-4-ethoxyphenyl)pyrimidin-4-yl)butanoicacid (0.32 g, 0.984 mmol), Hunig's base (0.45 mL, 1.86 mmol) and2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (0.449 g, 1.18 mmol) were combined in anhydrous DMF(10 mL). The reaction solution was stirred for 40 min at rt beforeintermediate (M) (0.248 g, 0.717 mmol), dissolved in a minimal amount ofDMF, was added dropwise. The resulting solution was allowed to stir atrt for 16 h. The reaction mixture was then evaporated and diluted withEtOAc and water. The organics were washed sequentially with saturatedaqueous NaHCO₃ and brine, dried over sodium sulfate, filtered and thefiltrate concentrated. The crude1-(4-(tert-butyl)benzyl)-2-(4-(2-(3-(cyanomethyl)-4-ethoxyphenyl)pyrimidin-4-yl)butanoyl)-N-ethylhydrazinecarboxamidethus obtained was used as is in the next step.

Step 5: To an EtOAc solution (10 mL) of1-(4-(tert-butyl)benzyl)-2-(4-(2-(3-(cyanomethyl)-4-ethoxyphenyl)pyrimidin-4-yl)butanoyl)-N-ethylhydrazinecarboxamide(0.547 g, 0.982 mmol) was added camphorsulfonic acid (0.228 g, 0.982mmol) and the resulting solution was heated at reflux for 16 h. Thereaction mixture was then diluted with EtOAc and brine. The organicswere separated and washed sequentially with 1M NaOH, water, and brine.The organic extract was then dried over sodium sulfate, filtered and thefiltrate concentrated. The residue was purified by column chromatographyusing 0%-50% gradient acetone/hexanes as eluent to afford 0.300 g (57%yield, three steps) of2-(5-(4-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyrimidin-2-yl)-2-ethoxyphenyl)acetonitrile.

Step 6: To a solution of2-(5-(4-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyrimidin-2-yl)-2-ethoxyphenyl)acetonitrile(0.100 g, 0.186 mmol) in ethylene glycol (6 mL) and water (1.5 mL) wasadded 18M KOH (0.104 mL, 1.86 mmol). The resulting mixture was thenstirred at 120° C. for 16 hrs. The reaction was quenched with 1 M aq.HCl (1.86 mL, 1.86 mmol) and the residue was diluted with EtOAc andwater. The organic layer was separated and washed further with water(2×). The organics were then filtered through a Na₂SO₄/paper plug andconcentrated. The organics were concentrated to afford 0.095 g (92%yield) of the title compound as a yellow solid. LCMS (ESI), M+H 558.

Example 27:2-(5-(6-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyrimidin-4-yl)-2-ethoxyphenyl)acetic acid

The title compound was prepared in an analogous fashion to Example 26but using instead the requisite commercially available4,6-dichloropyrimidine in the first step. LCMS (ESI), M+H 558.

Examples 28 (R=Me), 29 (R=Et) and 30 (R=nPr);(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-alkoxy-[1,1′-biphenyl]-4-yl)aceticacid

Example 31:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-hydroxy-[1,1′-biphenyl]-4-yl)aceticacid

Step 1: In a 75 mL screw-cap reaction flask equipped with a magneticstirrer was combined1-(4-(tert-butyl)benzyl)-4-ethyl-3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1H-1,2,4-triazol-5(4H)-one(300 mg, 0.60 mmol), methyl 2-(benzyloxy)-5-bromobenzoate (200 mg, 0.60mmol) and K₃PO₄ (330 mg, 2.4 mmol) in DME (4 mL) and water (2 mL). Theresulting biphasic mixture was then subsurface purged with N₂ for 15 minafter which, Pd₂(dba)₃ (14 mg, 0.015 mmol) and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (25 mg, 0.060 mmol) wereadded in one rapid portion. The now golden-yellow biphasic suspensionwas subsurface purged with N₂ for another 15 min before the vessel wastightly sealed and then heated at 85° C. for 15 h. The now dark orangereaction suspension was allowed to cool to RT, diluted with tert-butylmethyl ether and washed sequentially with 10% aq. HCl, water and brine.The organic extract thus obtained was then dried over Na₂SO₄,de-colorized with activated charcoal and finally filtered through a padof ether-wetted celite. The insolubles were rinsed further withtert-butyl methyl ether and the filtrate thus obtained was concentratedin vacuo. Purification of the crude product thus obtained by way ofcolumn chromatography (SiO₂, gradient elution, 4:1 Hex: EtOAc-EtOAc)furnished2-(3-(benzyloxy)-3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-yl)acetateas a pale yellow oil (190 mg, 49% yield).

Step 2: In a 500 mL Parr shaker flask was dissolved methyl2-(3-(benzyloxy)-3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-yl)acetate(190 mg, 29 mmol) from the previous step in MeOH (10 mL). To this wasthen added Pd/C (10% wt/wt wet, 120 mg, 0.06 mmol) and the resultingsuspension was thoroughly deoxygenated via subsurface purging withnitrogen. The reaction vessel was then connected to a Parr shaker andthe reaction suspension was shaken under 50 psi of H₂ for 5 h. Theexcess H₂ was discharged from the vessel and the reaction wasimmediately quenched with DCM. The deactivated catalyst was then removedvia filtration through a pad of DCM-wetted celite and the insolubleswere washed thoroughly with DCM. The filtrate thus obtained wasconcentrated in vacuo to furnish a pale yellow solid. Purification ofthe crude product thus obtained by way of column chromatography (SiO₂,gradient elution, 4:1 Hex: EtOAc-EtOAc) furnished methyl2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-hydroxy-[1,1′-biphenyl]-4-yl)acetateas a pale yellow solid (110 mg, 66% yield).

Step 3: In a 50 mL RBF equipped with a magnetic stirrer was added methyl2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-hydroxy-[1,1′-biphenyl]-4-yl)acetate(35 mg, 0.065 mmol) from the previous step in THF (1 mL) and MeOH (0.5mL). To this was then added 2N aq. LiOH (0.2 mL, 0.4 mmol) and theresulting solution was stirred at RT for 16 h. The volatiles were thenremoved in vacuo and the resulting residue was acidified with 1 N aq.HCl and extracted with DCM (3×10 mL). The combined organic extracts werethen washed further with water and brine, dried over Na₂SO₄ andfiltered. Concentration of the filtrate thus obtained in vacuo furnishedthe title compound as a white solid (33 mg, 66% yield). LC-MS: 528(M+H)⁺, 526 (M−H)⁺.

Example 32:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-isopropoxy-[1,1′-biphenyl]-3-yl)aceticacid

Example 33:2-(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-3-yl)aceticacid

Human PPARα Reporter Assay - Luciferase IC₅₀ Example Structure (nM)MS(ESI) 1

346 512 (M + H) 2

324 512 (M + H) 3

1333 498 (M + H) 4

110 498 (M + H) 5

137 582 (M + H) 6

58 554 (M − H) 7

77 538 (M + H) 8

487 538 (M + H) 9

548 528 (M + H) 10

211 542 (M + H) 11

48 570 (M + H) 12

302 610 (M + H) 13

197 542 (M + H) 14

234 552 (M + H) 15

122 618 (M + H) 16

141 582 (M + H) 17

83 530 (M + H) 18

750 556 (M + H) 19

119 556 (M + H) 20

896 623 (M + H) 21

610 556 (M + H) 22

64 592 (M + H) 23

659 646 (M + H) 24

2531 543 (M + H) 25

2293 521 (M + H) 26

1238 558 (M + H) 27

3431 558 (M + H) 28

140 542 (M + H) 29

59 556 (M + H) 30

36 570 (M + H) 31

528 (M + H) 32

570 (M + H) 33

599 (M + H)

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

1-32. (canceled)
 33. A method for treating cancer comprisingadministering a therapeutically effective amount of a compound ofFormula I, to a mammal in need thereof:

or a pharmaceutically acceptable salt thereof, wherein: A1 is phenyl,pyrimidinyl, or pyridinyl; A2 is A2a

wherein A2a is phenyl or pyridinyl; X is selected from the groupconsisting of —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄—, each optionally mono- ordi-substituted with halogen; Y is O; R¹ and R² are each independentlyselected from the group consisting of: (a) hydrogen, (b) halogen, (c)—O—(R⁷), (d) CF₃, (e) —C₁₋₆alkyl, R³ is selected from the groupconsisting of: (a) hydrogen, (b) —C₁₋₆alkyl, (c) —O—(R⁷), and (d)—N(R⁷)S(═O)₂(R⁸), wherein the alkyl portion of choice (b) is optionallysubstituted with halogen or hydroxyl; R⁴ and R^(4′) are eachindependently selected from the group consisting of: (a) hydrogen, (b)—O—R⁷, (c) —C(R⁷)(R⁸)OH, (d) —C₁₋₆alkyl-C(═O)OH, (e)—C₃₋₆cycloalkyl-C(═O)OH, (f) —C(═O)OH, (g) —NHS(═O)₂N(R⁷)(R⁸), (h)—C₃₋₆cycloalkyl, (i) —CF₃, (j)-heterocycle, (k) —C₁₋₆alkyl, and (l)halogen; with the proviso that at least one of R³, R⁴ and R^(4′) isother than hydrogen; R⁵ is selected from the group consisting of: (a)hydrogen, (b) —C₁₋₆alkyl, (c) —C₁₋₄alkyl(R⁷), wherein the alkyl portionof choices (b) and (c) is optionally substituted with halogen orC₁₋₄alkyl; R⁶ is selected from the group consisting of: (a)—C₁₋₆alkylaryl, (b) —C₁₋₆alkylheteroaryl, and (c) —C₁₋₄alkyl(R⁷);wherein the alkyl portion of choices (a), (b), and (c) is optionallysubstituted with halogen or C₁₋₄alkyl, and wherein the aryl portion ofchoice (a), and the heteroaryl portion of choices (b) are optionallymono- or di-substituted with substituents selected from halogen, nitro,—CF₃, C₁₋₆alkyl, C₁₋₆alkoxy, halo C₁₋₆alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkoxy, aryl, heteroaryl, heterocycle optionally substitutedwith halogen, —NH(C₁₋₆alkyl), —NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂,—N(C₃₋₆cycloalkyl)₂, —S(═O)_(o)C₁₋₆alkyl, S(═O)_(o)C₃₋₆cycloalkyl, andCN; R⁷ and R⁸ are each independently selected from the following: (a)hydrogen, (b) —C₁₋₆alkyl, (c) —C₃₋₆cycloalkyl, (d)-aryl, (e)-heteroaryl,and (f) CF₃; R⁹ and R¹⁰ are each independently selected from thefollowing (a) hydrogen, (b) —C₁₋₆alkyl, (d) halogen, (d) CF₃, and (e)C₁₋₆alkoxy wherein the alkyl of choice (b) is optionally mono-, di- ortri-substituted with halogen.
 34. The method according to claim 33, or apharmaceutically acceptable salt thereof, wherein X is —CH₂CH₂CH₂— or—CF₂CH₂CH₂—.
 35. The method according to claim 33, or a pharmaceuticallyacceptable salt thereof, wherein: A1 is phenyl, and R¹ and R² are eachhydrogen.
 36. The method according to claim 33, or a pharmaceuticallyacceptable salt thereof, wherein: A2 is A2a and A2a is phenyl.
 37. Themethod according to claim 33, or a pharmaceutically acceptable saltthereof, wherein: R³ is selected from the group consisting of: (a)hydrogen, (b) —O—(R⁷), (c) —N(R⁷)S(═O)₂(R⁸), and (d) —C₁₋₆alkyl; and R⁴and R^(4′) are each independently selected from the group consisting of:(a) hydrogen, (b) —O—(R⁷), (c) —C(R⁷)(R⁸)OH, (d) —C₁₋₆alkyl-C(═O)OH, (e)—C₃₋₆cycloalkyl-C(═O)OH, (f) —C(═O)OH, (g) C₃₋₆cycloalkyl, (h) CF₃, (i)heterocycle, (j) —C₁₋₆alkyl, and (k) halogen.
 38. The method accordingto claim 33, or a pharmaceutically acceptable salt thereof, wherein: R⁴and R^(4′) are each independently selected from the group consisting of:(a) —C(R⁷)(R⁸)OH, (b) —N(R⁷)S(═O)₂R⁸, (c) —O—(R⁷), (d)—C₁₋₆alkyl-C(═O)OH, (e) —C(═O)OH, (f) —C₃₋₆cycloalkyl, (g) CF₃, (h)heterocycle, (i) —C₁₋₆alkyl, and (j) halogen; R⁵ is selected from thegroup consisting of: (a) hydrogen, (b) —C₁₋₆alkyl, and (c)—C₁₋₄alkyl(R⁷); and R⁶ is selected from the group consisting of: (a)—C₁₋₆alkylaryl, (b) —C₁₋₆alkylheteroaryl, and (c) —C₁₋₆alkyl(R⁷); andwherein the aryl portion of choice (a), and the heteroaryl portion ofchoices (b) are optionally mono- or di-substituted with substituentsselected from halogen, nitro, —CF₃, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkoxy, aryl, heteroaryl,heterocycle optionally substituted with halogen, —NH(C₁₋₆alkyl),—NH(C₃₋₆cycloalkyl), —N(C₁₋₆alkyl)₂, —N(C₃₋₆cycloalkyl)₂, and CN. 39.The method according to claim 33, wherein the compound is a compound ofFormula 1b:

or a pharmaceutically acceptable salt thereof.
 40. The method of claim33, wherein the cancer is selected from prostate, breast, ovarian,liver, kidney, colon, pancreatic, human chronic lymphocytic leukemia andmelanoma.
 41. The method of claim 40, wherein the cancer is selectedfrom prostate, breast, and ovarian cancer.
 42. The method of claim 40,wherein the cancer is selected from liver, kidney, and colon cancer. 43.The method of claim 40, wherein the cancer is selected from humanchronic lymphocytic leukemia and melanoma.
 44. The method of claim 40,wherein the cancer is pancreatic cancer.
 45. A method for treatingcancer comprising administering a therapeutically effective amount of acompound selected from:2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)aceticacid,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-yl)aceticacid,3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-carboxylicacid,3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-carboxylicacid,1-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)cyclopropanecarboxylicacid,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)aceticacid,1-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)cyclopropanecarboxylicacid,1-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-4-yl)cyclopropanecarboxylicacid,3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methoxy-[1,1′-biphenyl]-3-carboxylicacid,3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-ethoxy-[1,1′-biphenyl]-3-carboxylicacid,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-propoxy-[1,1′-biphenyl]-3-yl)aceticacid,N-(6-(3-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)phenyl)pyridin-3-yl)benzenesulfonamide,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methoxy-[1,1′-biphenyl]-3-yl)aceticacid,1-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methyl-[1,1′-biphenyl]-3-yl)cyclopropanecarboxylicacid,2-(4-(benzyloxy)-3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)aceticacid,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-(cyclopropylmethoxy)-[1,1′-biphenyl]-3-yl)aceticacid,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-fluoro-[1,1′-biphenyl]-3-yl)aceticacid,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-6-ethoxy-[1,1′-biphenyl]-3-yl)aceticacid,3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-propoxy-[1,1′-biphenyl]-3-carboxylicacid,N-((3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1H-1,2,4-triazol-3-yl)propyl)-[1,1′-biphenyl]-3-yl)methyl)benzenesulfonamide,3-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-methoxy-[1,1′-biphenyl]-3-yl)propanoicacid,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1,1-difluoropropyl)-4-ethoxy-[1,1′-biphenyl]-3-yl)aceticacid,N-(6-(3-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1H-1,2,4-triazol-3-yl)-1,1-difluoropropyl)phenyl)pyridin-3-yl)benzenesulfonamide,2-(5-(6-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyridin-2-yl)-2-methoxyphenyl)aceticacid,3-(3-(3′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)propyl)-1-(4-(tert-butyl)benzyl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one,2-(5-(4-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyrimidin-2-yl)-2-ethoxyphenyl)aceticacid,2-(5-(6-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)pyrimidin-4-yl)-2-ethoxyphenyl)aceticacid,(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-methoxy-[1,1′-biphenyl]-4-yl)aceticacid,(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-ethoxy-[1,1′-biphenyl]-4-yl)aceticacid,(3′-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-propoxy-[1,1′-biphenyl]-4-yl)aceticacid,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-3-hydroxy-[1,1′-biphenyl]-4-yl)aceticacid,2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-isopropoxy-[1,1′-biphenyl]-3-yl)acetic acid, and2-(3′-(3-(1-(4-(tert-butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-4-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-3-yl)aceticacid, or a pharmaceutically acceptable salt of any of the foregoing, toa mammal in need thereof.
 46. The method of claim 45, wherein the canceris selected from prostate, breast, ovarian, liver, kidney, colon,pancreatic, human chronic lymphocytic leukemia and melanoma.
 47. Themethod of claim 46, wherein the cancer is selected from prostate,breast, and ovarian cancer.
 48. The method of claim 46, wherein thecancer is pancreatic cancer.
 49. The method of claim 46, wherein thecancer is colon cancer.
 50. The method of claim 46, wherein the canceris selected from liver and kidney cancer.
 51. The method of claim 46,wherein the cancer is human chronic lymphocytic leukemia.
 52. The methodof claim 46, wherein the cancer is melanoma.